NZ631318B2

NZ631318B2 - Method of weight management

Info

Publication number: NZ631318B2
Application number: NZ631318A
Authority: NZ
Inventors: Matilde Sanchez; William R Shanahan
Original assignee: Arena Pharmaceuticals Inc
Priority date: 2012-10-09
Filing date: 2012-11-06
Publication date: 2017-08-01

Abstract

Disclosed is the use of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof in the manufacture of a medicament for therapeutic treatments including weight management, decreasing food intake, inducing satiety or treating obesity, wherein: -the medicament is provided for oral administration at a dose of 20mg per day -the medicament is provided for administration in combination with a reduced-calorie diet -the subject has been selected for treatment as previously having been determined to have achieved at least 5% weight loss within 12 weeks of treatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine at a dose of 20mg, and whereby achievement of at least 5% weight loss by week 12 correlates with a likelihood of the individual achieving an additional decrease in assessment of weight after about one year -wherein the subject has an initial BMI of over 27 prior to treatment wherein: -the medicament is provided for oral administration at a dose of 20mg per day -the medicament is provided for administration in combination with a reduced-calorie diet -the subject has been selected for treatment as previously having been determined to have achieved at least 5% weight loss within 12 weeks of treatment with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine at a dose of 20mg, and whereby achievement of at least 5% weight loss by week 12 correlates with a likelihood of the individual achieving an additional decrease in assessment of weight after about one year -wherein the subject has an initial BMI of over 27 prior to treatment

Description

METHOD OF WEIGHT MANAGEMENT CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) ofU.S. ional Serial No. 61/711,413, filed r 9, 2012, the contents ofwhich are incorporated by reference in their entirety into the current disclosure. y is a life-threatening disorder in which there is an increased risk of morbidity and mortality arising from concomitant diseases such as typ e II diabetes, hyp ertension, stroke, cancer and gallbladder disease.

Obesity is now a major healthcare issue in the Western World and singly in some third world ies. The increase in numbers ofobese people is due largely to the increasing preference for high fat content foods but also the decrease in activity in most people's lives. Currently about 30% ofthe population ofthe USA is now considered obese.

Whether someone is classified as overweight or obese is generally determined on the basis oftheir body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m2). Thus, the units ofBMI are kg/m2 and it is possible to ate the BMI range ated with minimum mortality in each decade of life. Overweight is defined as a BMI in the range 25-30 kg/m2, and obesity as a BMI greater than 30 kg/m2 (see table below).

CLASSIFICATION OF WEIGHT BY BODY MASS INDEX (BMI) BMI CLASSIFICATION < 18.5 eight 18.5-24.9 Normal .0-29.9 Overweight .0-34.9 Obesity (Class I) .0-39.9 Obesity (Class II) >40 Extreme Obesity (Class III) As the BMI increases there is an increased risk h from a variety of causes that are independent ofother risk factors. The most common diseases associated with obesity are cardiovascular disease (particularly hyp ertension), diabetes ( obesity ation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm aggravates the development ofdiabetes), gall bladder e (particularly cancer) and diseases ofreproduction. The strength ofthe link between obesity and specific ions varies. One ofthe strongest is the link with type 2 diabetes. Excess body fat underlies 64% s ofdiabetes in men and 77% s in women (Seidell, Semin Vase Med :3-14 (2005)). Research has shown that even a modest ion in body weight can correspond to a significant reduction in the risk ofdeveloping coronary heart disease.

There are problems however with the BMI definition in that it does not take into account the proportion ofbody mass that is muscle in relation to fat (adipose tissue). To account for this, obesity can also be defined on the basis ofbody fat content: greater than 25% in males and greater than 30% in females.

Obesity considerably increases the risk ofdeveloping cardiovascular diseases as well. Coronary insufficiency, atheromatous disease, and cardiac insufficiency are at the forefront ofthe cardiovascular complications d by obesity. It is estimated that ifthe entire population had an ideal weight, the risk ofcoronary insufficiency would decrease by % and the risk ofcardiac insufficiency and bral vascular accidents would decrease by 35%. The incidence ofcoronary diseases is doubled in subjects less than 50 years ofage who are 30% overweight. The diabetes patient faces a 30% reduced lifespan. After age 45, people with diabetes are about three times more likely than people without diabetes to have significant heart disease and up to five times more likely to have a stroke. These findings emphasize the inter-relations between risks factors for diabetes and coronary heart disease and the potential value ofan integrated approach to the prevention ofthese conditions based on the prevention ofobesity (Perry, I. J., et al., BMJ310, 560-564 (1995)).

Diabetes has also been implicated in the development ey disease, eye diseases and nervous system ms. Kidney disease, also called nephropathy, occurs when the 's "filter mechanism" is d and protein leaks into urine in ive amounts and eventually the kidney fails. Diabetes is also a g cause of damage to the retina at the back ofthe eye and increases risk ofcataracts and glaucoma.

Finally, diabetes is associated with nerve , especially in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections. Taken together, diabetes complications are one ofthe nation's leading causes ofdeath.

The first line oftreatment is to offer diet and life style advice to patients such as reducing the fat content oftheir diet and increasing their physical activity.

[Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm ation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm However, many patients find this difficult and need additional help from drug therapy to maintain results from these efforts.

Most currently marketed products have been unsuccessful as treatments for obesity because ofa lack ofefficacy or ptable side-effect profiles. The most successful drug so far was the indirectly acting 5-hydroxytryptamine (5-HT) t dfenfluramine (Redux™) but reports ofcardiac valve defects in up to one third ofpatients led to its withdrawal by the FDA in 1998.

In addition, two drugs have been launched in the USA and : Orlistat (Xenical™), a drug that prevents absorption offat by the inhibition ofpancreatic lipase, and Sibutramine (Reductil™), a 5-HT/noradrenaline re-uptake inhibitor. r, side effects associated with these products may limit their long-term utility. Treatment with XenicalTM is reported to induce gastrointestinal distress in some patients, while Sibutramine has been associated with raised blood pressure in some patients.

Serotonin (5-HT) neurotransmission plays an important role in numerous physiological processes both in physical and in psychiatric ers. 5-HT has been implicated in the regulation offeeding behavior. 5-HT is believed to work by inducing a feeling ofsatiety, such that a t with ed 5-HT stops eating earlier and fewer calories are consumed. It has been shown that a stimulatory action of5-HT on the 5-HT2c receptor plays an important role in the control ofeating and in the anti-obesity effect ofdfenfluramine.

As the 5-HT2c receptor is expressed in high density in the brain ly in the limbic structures, extrapyramidal pathways, thalamus and hypothalamus i.e. PVN and DMH, and predominantly in the choroid ) and is expressed in low density or is absent in peripheral tissues, a selective 5-HT2c receptor agonist can be a more ive and safe anti-obesity agent. Also, 5-HT2c knockout mice are overweight with cognitive impairment and tibility to seizure.

It is believed that the 5-HT2c receptor may play a role in obsessive compulsive disorder, some forms ofdepression, and epilepsy. Accordingly, agonists can have anti-panic properties, and ties useful for the treatment of sexual dysfunction.

In sum, the 5-HT2c receptor is a receptor target for the treatment ofobesity and psychiatric disorders, and it can be seen that there is a need for selective 5-HT2c ts which safely decrease food intake and body weight.

Compounds and formulations presented herein can comprise the selective -HT2c- or agonist (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm (Compound 1), and are useful for, inter alia, weight management, including weight loss and the maintenance ht loss. Compound 1 is sed in PCT patent publication W02003/086303, which is incorporated herein by reference in its entirety.Cl'(J(J I NH ::::::,....

Various synthetic routes to (R)chloromethyl-2,3,4,5-tetrahydro-lH- 3-benzazepine, its d salts, enantiomers, crystalline forms, and intermediates, have been reported in , , , WO 2008/070111, and each ofwhich is incorporated herein by reference in its entirety.

Combinations of (R)Chloromethyl-2,3,4,5-tetrahydro-lH benzazepine with other agents, including without limitation, phentermine, and uses of such combinations in therapy are described in , which is incorporated herein by reference in its entirety.

(R)Chloromethyl-2,3,4,5-tetrahydro-lHbenzazepine hydrochloride (lorcaserin hydrochloride) is an agonist ofthe 5-HT2c or and shows effectiveness at reducing obesity in animal models and . In December 2009, Arena ceuticals submitted a New Drug Application, or NDA, for lorcaserin to the FDA.

The NDA submission is based on an extensive data package from lorcaserin'sclinical development program that includes 18 clinical trials totaling 8,576 patients. The pivotal phase 3 clinical trial program evaluated nearly 7,200 patients treated for up to two years, and showed that erin consistently produced significant weight loss with excellent tolerability. About two-thirds ents achieved at least 5% weight loss and over onethird achieved at least 10% weight loss. On average, patients lost 17 to 18 pounds or about 8% oftheir weight. Secondary endpoints, including body composition, lipids, vascular risk factors and glycemic ters improved compared to placebo. In on, heart rate and blood pressure went down. Lorcaserin did not increase the risk of cardiac valvulopathy. Lorcaserin improved quality of life, and there was no signal for sion or suicidal ideation. The only adverse event that exceeded the placebo rate by % was generally mild or moderate, ent headache. Based on a normal BMI of25, patients in the first phase 3 trial lost about one-third oftheir excess body weight. The average weight loss was 35 pounds or 16% of body weight for the top quartile of patients in the second phase 3 trial.

There exists a need for safely treating individuals who are in need of treatment with lorcaserin. The present disclosure satisfies this need and provides related ages as well.

SUMMARY [0019a] In a first aspect, the present invention provides the use of (R)chloromethyl- 2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof in the manufacture of a ment for the therapeutic ent of an individual, wherein said therapeutic treatment is weight management; wherein said ment is provided for oral administration to the individual at a dose equivalent to 20 mg of (R) chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride per day; wherein said medicament is provided for stration in combination with a reduced-calorie diet; wherein said individual has been selected for treatment as usly being determined to have achieved at least 5% weight loss within 12 weeks of treatment with (R)chloro methyl-2,3,4,5-tetrahydro-1Hbenzazepine or a ceutically acceptable salt, solvate or hydrate thereof at a dose equivalent to 20 mg of (R)chloromethyl-2,3,4,5-tetrahydro-1H- 3-benzazepine hydrochloride per day, whereby ement of at least 5% weight loss by week 12 correlates with a likelihood of the individual achieving an additional decrease in an assessment of weight after about one year; and wherein said individual has an l body mass index (BMI) of >27 kg/m2 prior to treatment with (R)chloromethyl-2,3,4,5- tetrahydro-1Hbenzazepine or a ceutically acceptable salt, solvate or hydrate thereof. [0019b] In a second aspect, the present invention provides the use of chloro methyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof in the manufacture of a medicament for the eutic treatment of an individual, wherein said therapeutic treatment is decreasing food intake; wherein said medicament is provided for oral administration to the individual at a dose equivalent to 20 mg of chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride per day; wherein said medicament is provided for administration in combination with a reducedcalorie diet; wherein said individual has been selected for treatment as previously being determined to have achieved at least 5% weight loss within 12 weeks of treatment with (R) chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, e or hydrate thereof at a dose equivalent to 20 mg of (R)chloromethyl-2,3,4,5- tetrahydro-1Hbenzazepine hloride per day, whereby ement of at least 5% weight loss by week 12 correlates with a likelihood of the individual achieving an additional se in an assessment of weight after about one year; and wherein said individual has an initial body mass index (BMI) of >27 kg/m2 prior to treatment with (R)chloromethyl- 2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof. [0019c] In a third aspect, the present invention provides the use of (R)chloro methyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof in the manufacture of a medicament for the therapeutic treatment of an individual, wherein said therapeutic treatment is inducing satiety; wherein said ment is provided for oral administration to the individual at a dose equivalent to 20 mg of (R) methyl-2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride per day; wherein said medicament is provided for administration in combination with a reduced-calorie diet; wherein said individual has been selected for treatment as previously being determined to have achieved at least 5% weight loss within 12 weeks of treatment with (R)chloro methyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof at a dose equivalent to 20 mg of (R)chloromethyl-2,3,4,5-tetrahydro-1H- 3-benzazepine hydrochloride per day, y achievement of at least 5% weight loss by week 12 correlates with a likelihood of the dual achieving an additional decrease in an assessment of weight after about one year; and wherein said individual has an initial body mass index (BMI) of >27 kg/m2 prior to treatment with chloromethyl-2,3,4,5- tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate f. [0019d] In a fourth aspect, the present invention provides the use of (R)chloro methyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof in the manufacture of a ment for the therapeutic treatment of an individual, wherein said therapeutic treatment is the treatment of obesity; wherein said medicament is provided for oral administration to the individual at a dose equivalent to 20 mg of (R)chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride per day; wherein said medicament is provided for stration in combination with a reducedcalorie diet; wherein said individual has been selected for treatment as previously being determined to have achieved at least 5% weight loss within 12 weeks of treatment with (R) chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof at a dose equivalent to 20 mg of (R)chloromethyl-2,3,4,5- tetrahydro-1Hbenzazepine hydrochloride per day, whereby achievement of at least 5% weight loss by week 12 correlates with a likelihood of the individual achieving an additional decrease in an assessment of weight after about one year; and wherein said individual has an initial body mass index (BMI) of >30 kg/m2 prior to treatment with (R)chloromethyl- 2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Provided is a method of ining if an individual is a responder to treatment with (R)chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the steps of: measuring an individual's responsiveness to (R)chloromethyl-2,3,4,5- tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof after a first time period of administration of (R)chloromethyl-2,3,4,5-tetrahydro-1H benzazepine or a pharmaceutically acceptable salt, solvate or hydrate f to the dual, wherein if the individual has achieved a old effect after said first time period of stration, the individual is a responder.

Also provided is a method for selecting an individual for treatment with (R) chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a ceutically acceptable salt, e or hydrate thereof from a plurality of duals in need of weight management, comprising: measuring an individual's responsiveness to (R)chloromethyl-2,3,4,5- tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof after a first time period of administration of (R)chloromethyl-2,3,4,5-tetrahydro-1H benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof to the individual; selecting the individual for treatment with (R)chloromethyl-2,3,4,5-tetrahydro- 1Hbenzazepine or a pharmaceutically able salt, solvate or hydrate thereof if the individual has achieved a threshold effect after said first time period of administration.

Also provided is a method for weight management in an dual in need thereof, comprising the steps of: [Annotation] kjm None set by kjm ation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm administering a therapeutically effective amount of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto an individual, wherein said individual has previously been determined to be a der or selected for treatment according to any one ofthe methods described herein.

Also provided is a method for weight management in an individual in need thereof, comprising the steps of: administering to the individual a therapeutically effective amount 8-chloro- 1-methyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate f; determining r the individual is a responder or is ed for treatment according to any one ofthe methods described herein; and continuing administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro- IH epine or a pharmaceutically acceptable salt, solvate or hydrate thereofifthe dual is identified as a responder, or modifying the administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro-IH- 3-benzazepine or a pharmaceutically acceptable salt, solvate or e thereofto the individual ifthe individual is not fied as a responder.

Also provided is a method for decreasing food intake in an individual in need thereof, comprising the steps of: stering a therapeutically effective amount of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto an individual, wherein said individual has previously been determined to be a responder or selected for treatment according to any one ofthe s described herein.

Also provided is a method for decreasing food intake in an individual in need thereof, comprising the steps of: administering to the individual a therapeutically effective amount 8-chloro- 1-methyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; determining whether the individual is a responder or is selected for treatment according to the method ofany one ofthe methods described herein; and [Annotation] kjm None set by kjm ation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm continuing administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro- IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofifthe individual is identified as a responder, or modifying the administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro-IH- 3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate fto the individual ifthe individual is not identified as a responder.

Also provided is a method for inducing satiety in an individual in need thereof, comprising the steps of: administering a therapeutically effective amount of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or e thereofto an individual, wherein said individual has previously been determined to be a responder or selected for treatment according to any one ofthe methods described herein.

Also provided is a method for ng satiety in an individual in need thereof, comprising the steps of: administering to the dual a therapeutically effective amount of(R)chloro- 1-methyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; determining whether the individual is a responder or is selected for treatment according to the method ofany one ofthe s described herein; and continuing administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro- IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofifthe individual is fied as a der, or modifying the administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro-IH- 3-benzazepine or a ceutically acceptable salt, solvate or hydrate fto the individual ifthe dual is not identified as a responder.

Also provided is a method for the treatment ofobesity in an individual in need thereof, comprising the steps of: administering a therapeutically effective amount of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, e or hydrate thereofto an individual, wherein said individual has previously been determined to be a der or selected for treatment according to any one ofthe methods described herein.

[Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm ionNone set by kjm [Annotation] kjm ed set by kjm Also provided is a method for the treatment ofobesity in an individual in need thereof, comprising the steps of: administering to the individual a therapeutically effective amount of(R)chloro- 1-methyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate f; determining whether the individual is a responder or is selected for ent according to the method ofany one ofthe methods described herein; and continuing administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro- IH benzazepine or a pharmaceutically acceptable salt, solvate or e thereofifthe individual is identified as a responder, or modifying the administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro-IH- 3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate fto the individual ifthe individual is not identified as a responder.

Also provided is a method for the prevention ofobesity in an individual in need thereof, comprising the steps of: administering a therapeutically effective amount of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto an individual, wherein said dual has previously been determined to a responder or selected for treatment ing to any one ofthe methods described herein.

Also provided is a method for the prevention ofobesity in an individual in need thereof, sing the steps of: administering to the individual a therapeutically effective amount of(R)chloro- 1-methyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; ining whether the individual is a responder or is selected for treatment according to any one ofthe methods described ; and continuing administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro- IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofifthe dual is identified as a responder, or modifying the administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro-IH- 3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto the dual ifthe individual is not identified as a responder.

[Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm ed set by kjm Also ed is a nd for use in any ofthe methods described herein.

Also provided is a composition for use in a method ofweight management in an individual, comprising a therapeutically effective amount of(R)chloromethyl-2,3,4,5-tetrahydrolHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein the individual has previously been determined to be a responder or selected for treatment according to any one ofthe methods described herein.

Also provided is a kit for use in a method ofweight management in an individual, sing a therapeutically ive amount of(R)chloromethyl-2,3,4,5-tetrahydrolHbenzazepine or a pharmaceutically able salt, solvate or hydrate thereof; and instructions indicating that the (R)chloromethyl-2,3,4,5-tetrahydro-lH benzazepine or a pharmaceutically acceptable salt, e or e f is to be administered to an individual who has previously been determined to a responder or selected for treatment according to any one ofthe methods described herein.

BRIEF DESCRIPTION OF FIGURES Figure 1 provides data for the percentage ofpatients achieving 2:5% weight loss or 2:10% weight at 52 weeks for both responders and sponders. The top panel is for patients with type 2 diabetes mellitus. The bottom panel is for patients without type 2 diabetes mellitus.

Figure 2 shows the Week 52 weight loss in lorcaserin Week 12 responders with type 2 diabetes was 9.3kg (20 lbs), with 71 % and 36% achieving 5% and 10% weight loss, respectively. Figure 2 shows weight loss through Week 52 for Week 12 ders and non-responder with and without diabetes.

DETAILED DESCRIPTION As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

INDIVIDUAL: As used herein, an "individual" is a human. An individual can be an adult or prepubertal ( a child) and can be ofany gender. The individual can be a patient or other individual seeking treatment. The methods sed herein can also apply to non-human mammals such as livestock or pets.

[Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm ation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm PLURALITY OF INDIVIDUALS: As used herein, a "plurality of individuals" means more than one individual.

STERING: As used herein, "administering" means to provide a compound or other therapy, remedy or treatment. For e, a health care practitioner can ly provide a compound to an dual in the form ofa sample, or can indirectly provide a compound to an individual by providing an oral or written prescription for the nd. Also, for example, an individual can obtain a compound by themselves without the involvement ofa health care practitioner. Administration of the compound may or may not involve the individual actually internalizing the compound. In the case where an individual internalizes the compound the body is transformed by the nd in some way.

PRESCRIBING: As used herein, "prescribing" means to order, ize or recommend the use of a drug or other therapy, remedy or treatment. In some ments, a health care practitioner can orally advise, recommend or authorize the use ofa compound, dosage regimen or other treatment to an individual. In this case the health care practitioner may or may not provide a prescription for the compound, dosage regimen or treatment. Further, the health care practitioner may or may not provide the recommended compound or treatment. For example, the health care practitioner can advise the individual where to obtain the compound without providing the compound. In some embodiments, a health care practitioner can provide a prescription for the compound, dosage regimen or treatment to the individual. For example, a health care practitioner can give a written or oral prescription to an individual. A prescription can be written on paper or on onic media such as a computer file, for example, on a hand held computer device. For example, a health care tioner can orm a piece of paper or electronic media with a prescription for a compound, dosage n or treatment. In addition, a prescription can be called in (oral) or faxed in (written) to a pharmacy or a dispensary. In some embodiments, a sample ofthe compound or treatment can be given to the individual. As used herein, giving a sample ofa compound constitutes an implicit prescription for the nd. Different health care systems around the world use different methods for prescribing and administering compounds or treatments and these methods are encompassed by the disclosure.

A prescription can include, for example, an individual'sname and/or fying information such as date ofbirth. In addition, for example, a prescription can [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm ation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm ionNone set by kjm [Annotation] kjm Unmarked set by kjm include, the medication name, medication strength, dose, frequency of administration, route nistration, number or amount to be discpensed, number ofrefills, physician name, ian signature. Further, for example, a prescription can include a DEA number or state number.

A healthcare practitioner can include, for example, a physician, nurse, nurse practitioner or other related health care professional who can prescribe or administer compounds (drugs) for weight management. In addition, a healthcare practitioner can include anyone who can end, prescribe, administer or prevent an individual from receiving a compound or drug including, for example, an insurance provider.

PREVENT, PREVENTING, OR PREVENTION: As used herein, the term "prevent," "preventing" or "prevention" such as tion ity means prevention ofthe occurrence or onset ofone or more symptoms associated with a particular disorder and does not necessarily mean the complete prevention ofa disorder.

For example, the term "prevent," "preventing" and "prevention" refers to the administration oftherapy on a prophylactic or preventative basis to an individual who may ultimately manifest at least one m ofa e or condition but who has not yet done so. Such individuals can be identified on the basis ofrisk factors that are known to correlate with the subsequent occurrence ofthe disease. Alternatively, prevention therapy can be administered without prior identification ofa risk factor, as a lactic measure. Delaying the onset of the at least one symptom can also be considered prevention or prophylaxis.

TREAT, NG, OR ENT: As used herein the term "treat," "treating" or "treatment" refers to the administration oftherapy to an individual who already manifests at least one symptom ofa disease or condition or who has usly manifested at least one symptom ofa disease or condition. For example, "treating" can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, ting the disease or condition, e.g., arresting the development ofthe disease or condition, relieving the disease or condition, causing regression ofthe disease or condition, relieving a ion caused by the disease or condition, or stopping the symptoms ofthe disease or condition either prophylacticly and/or therapeutically. For e, the term ing" in reference to a disorder means a reduction in severity of one or more symptoms associated with a particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all ms associated [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm ionNone set by kjm ation] kjm Unmarked set by kjm with a disorder and does not necessarily mean a complete reduction in the severity ofone or more symptoms associated with a disorder. For example, a method for treatment of obesity can result in weight loss; however, the weight loss does not need to be enough such that the individual is no longer obese. It has been shown that even modest decreases in weight or related parameters such as BMI, waist circumference and percent body fat, can result in improvement ofhealth, for example, lower blood pressure, improved blood lipid profiles, or a ion in sleep apnea.

WEIGHT MANAGEMENT: As used herein, the term "weight management" means controlling body weight and in the context ofthe present disclosure is directed toward weight loss and the maintenance ofweight loss (also called weight maintenance herein). In addition to controlling body weight, weight management includes controlling parameters related to body weight, for e, BMI, t body fat and waist circumference. For example, weight management for an individual who is overweight or obese can mean losing weight with the goal ofkeeping weight in a healthier range. Also, for e, weight management for an individual who is overweight or obese can include losing body fat or circumference around the waist with or without the loss ofbody weight. Maintenance ofweight loss (weight maintenance) includes preventing, reducing or controlling weight gain after weight loss. It is well known that weight gain often occurs after weight loss. Weight loss can occur, for example, from dieting, sing, illness, drug treatment, surgery or any ation of these methods, but often an individual that has lost weight will regain some or all ofthe lost weight. Therefore, weight maintenance in an individual who has lost weight can include preventing weight gain after weight loss, reducing the amount ofweigh gained after weight loss, controlling weight gain after weight loss or slowing the rate ofweight gain after weight loss. As used herein, "weight management in an dual in need thereof'refers to a judgment made by a healthcare tioner that an individual requires or will benefit from weight management treatment. This judgment is made based on a variety ors that are in the realm ofa healthcare practitioner'sexpertise, but that includes the knowledge that the individual has a condition that is ble by the methods disclosed herein.

DECREASING FOOD INTAKE: As used herein, "decreasing food intake in an individual in need thereof'refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from sing food intake. This [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm judgment is made based on a variety offactors that are in the realm ofa healthcare tioner'sexpertise, but that includes the knowledge that the individual has a condition, for example, obesity, that is treatable by the methods disclosed herein. In some embodiments, an individual in need of decreasing food intake is an individual who is ight. In some embodiments, an individual in need ofdecreasing food intake is an individual who is obese.

SATIETY: As used herein, "satiety" is the quality or state ofbeing fed or ied to or beyond capacity. Satiety is a feeling that an individual has and so it is often determined by asking the individual, orally or in writing, ifthey feel full, sated, or satisfied at timed intervals during a meal. For e, an individual who feels sated may report feeling full, g a decreased or absent hunger, feeling a decreased or absent desire to eat, or feeling a lack ofdrive to eat. While fullness is a physical ion, satiety is a mental feeling. An individual who feels full, sated or ied is more likely to stop eating and therefore inducing satiety can result in a decrease in food intake in an individual. As used herein, "inducing satiety in an individual in need thereof'refers to a judgment made by a healthcare practitioner that an individual es or will benefit from inducing satiety. This judgment is made based on a y offactors that are in the realm of a healthcare practitioner'sexpertise, but that es the knowledge that the individual has a ion, for example, obesity, that is treatable by the methods ofthe sure.

TREATMENT OF OBESITY: As used herein, "treatment ofobesity in an individual in need thereof'refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from treatment ofobesity. This judgment is made based on a variety offactors that are in the realm ofa healthcare practitioner's expertise, but that includes the knowledge that the individual has a condition that is ble by the methods of the disclosure. To determine whether an individual is obese one can determine a body weight, a body mass index (BMI), a waist circumference or a body fat percentage ofthe individual to determine ifthe individual meets a body weight threshold, a BMI threshold, a waist circumference threshold or a body fat percentage threshold.

PREVENTION OF OBESITY: As used herein, "prevention ofobesity in an individual in need thereof'refers to a nt made by a healthcare tioner that an individual requires or will benefit from prevention ofobesity. This judgment is made based on a variety offactors that are in the realm ofa healthcare tioner's expertise, but that includes the knowledge that the individual has a condition that is treatable by the [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm ed set by kjm methods disclosed herein. In some embodiments, an individual in need ofprevention of obesity is an individual who is overweight (also called pre-obese). In some embodiments, an individual in need ofprevention ofobesity is an individual who has a family history of obesity. To determine whether an dual is overweight one can determine a body weight, a body mass index (BMI), a waist circumference or a body fat percentage ofthe individual to ine ifthe individual meets a body weight threshold, a BMI threshold, a waist ference threshold or a body fat percentage threshold.

ADVERSE EVENT OR TOXIC EVENT: As used herein, an "adverse event" or "toxic event" is any untoward medical ence that may present itself during treatment. Adverse events associated with treatment with Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereofinclude, for example, nal pain, diarrhea, dyspepsia, stomach discomfort, and ing renal impairment, dizziness, headache. Other possible e effects based on observations from studies in monkeys include , decreased food intake, weight loss, decreased activity, spontaneous penile erection, tremors or es. Additional possible adverse effects include, for example, , blurred vision, paresthesias, dry mouth and fatigue.

In the methods disclosed herein, the term adverse event can be replaced by other more general terms such as toxicity. The term "reducing the risk" ofan e event means reducing the probability that an adverse event or toxic event could occur.

As used herein, the term "phentermine" refers to 1,1-dimethylphenylethylamine , including phentermine tives and pharmaceutically acceptable salts thereof, such as, but not limited to, chlorphentermine (2-(4-chloro-phenyl)-1,1-dimethylethylamine ) and the like. In one embodiment, phentermine is in the HCl salt form of 1,1- dimethylphenyl-ethylamine.

As used herein, the term "greater than" is used interchangeably with the symbol > and the term less than is used interchangeably with the symbol <. Likewise the term less than or equal to is interchangeably with the symbol :S.

When an integer is used in a method disclosed herein, the term "about" can be ed before the integer. For example, the term "greater than 29 kg/m2" can be substituted with "greater than about 29 kg/m2".

As used in the present specification, the following abbreviations are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[Annotation] kjm None set by kjm [Annotation] kjm ionNone set by kjm ation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm ed set by kjm oc Degrees Celsius AIC Glycated hemoglobin AUC Area under curve BID Twice a day BL Baseline BMI Body Mass Index BP Blood pressure BPM/bpm Beats per minute CI Confidence interval cm Centimeter DBP Diastolic blood pressure DEA Drug Enforcement Administration dL Deciliter DMH Dorsomedial hypothalamic nucleus DSC ential scanning calorimetry eq. equivalents FDA Food and Drug Administration FPG g Plasma Glucose IFG Impaired Fasting Glucose g Gram h Hour HDL High-density lipoprotein Kg/kg Kilogram lbs Pounds LDL Low-density lipoprotein M Molar mL Square Meter mg Milligram mm Minute MITT Modified intention to treat LOCF Last observation carried forward mmHg Millimeters ofMercury [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm N Number NDA New Drug Application PVN Paraventricular alamic nucleus QD Once a day ROCC Receiver operating characteristic curve SBP Systolic blood pressure T2DM Type-two Diabetes Mellitus TGA Thermogravimetric Analysis W12 Week 12 W52 Week52 wt Weight XRPD X-ray powder diffraction Throughout this specification, unless the context es otherwise, the word "comprise", or variations such as "comprises" or "comprising" will be understood to imply the inclusion ofa stated step or element or integer or group s or elements or integers but not the exclusion ofany other step or t or integer or group of elements or integers.

Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition er, group of steps or group ofcompositions ofmatter shall be taken to encompass one and a plurality (i.e. one or more) ofthose steps, compositions er, groups ofsteps or group of compositions ofmatter.

Each embodiment described herein is to be d mutatis mutandis to each and every other embodiment unless specifically stated otherwise.

Those skilled in the art will iate that the invention(s) described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention(s) includes all such variations and modifications. The invention(s) also includes all ofthe steps, features, compositions and compounds referred to or indicated in this specification, dually or collectively, and any and all combinations or any two or more of said steps or features unless specifically stated ise.

The present invention(s) is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose ofexemplification [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm ation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm only. Functionally-equivalent products, compositions and methods are clearly within the scope ofthe invention(s), as described herein.

It is appreciated that certain features ofthe invention(s), which are, for clarity, described in the context ofseparate embodiments, can also be provided in combination in a single embodiment. Conversely, various features ofthe invention(s), which are, for brevity, bed in the t ofa single embodiment, can also be provided separately or in any suitable subcombination. For example, a method that recites prescribing or administering (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine can be separated into two methods; one reciting prescribing (R)chloro methyl-2,3,4,5-tetrahydro-IHbenzazepine and the other reciting administering (R) chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine. In addition, for example, a method that recites prescribing (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine and a separate method ofthe invention reciting administering (R)chloro -2,3,4,5-tetrahydro-IHbenzazepine can be combined into a single method reciting prescribing and/or administering (R)chloromethyl-2,3,4,5- tetrahydro-IH benzazepine.

Provided is a method ofdetermining if an individual is a der to treatment with (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or e thereof, comprising the steps of: measuring an individual'sresponsiveness to (R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, e or hydrate thereof after a first time period ofadministration of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a ceutically able salt, solvate or hydrate thereofto the individual, wherein ifthe dual has achieved a threshold effect after said first time period ofadministration, the individual is a responder. ed is a method rmining if an dual is a responder to treatment with (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the steps of: administering (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto an individual for a first time period ofadministration; [Annotation] kjm None set by kjm [Annotation] kjm ionNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm measuring the individual'sresponsiveness to (R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically able salt, solvate or hydrate thereof; wherein ifthe individual has ed a threshold effect after said first time period ofadministration, the individual is a responder.

Also provided is a method for ing an individual for treatment with (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, e or hydrate thereof from a plurality ofindividuals in need ofweight management, comprising: measuring an dual'sresponsiveness to (R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof after a first time period ofadministration of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto the individual; and selecting the individual for treatment with (R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofifthe dual has achieved a threshold effect after said first time period of administration.

Also provided is a method for selecting an individual for ent with (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof from a plurality ofindividuals in need ht management, sing: administering (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto an dual for a first time period ofadministration; measuring the individual'sresponsiveness to (R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; and ing the individual for treatment with (R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof ifthe individual has achieved a threshold effect after said first time period of administration. ation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm Also provided is a method for assisting in the ion ofan individual for treatment with (R)chloromethyl-2,3,4,5-tetrahydro-lHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof from a plurality ofindividuals in need ofweight management, comprising: measuring an individual'sresponsiveness to (R)chloromethyl-2,3,4,5- tetrahydro-lHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate f after a first time period ofadministration of(R)chloromethyl-2,3,4,5- tetrahydro-lHbenzazepine or a pharmaceutically able salt, e or hydrate thereofto the individual, wherein ifthe measurement ofthe individual'sresponsiveness indicates exceeds a threshold effect after said first time period ofadministration then the individual is suitable for prescription ofa therapeutically effective amount ofwith (R) chloromethyl-2,3,4,5-tetrahydro- enzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In some embodiments, an individual in need ofweight management is an individual who is overweight. In some embodiments, an dual in need ofweight management is an dual who has excess visceral adiposity. In some embodiments, an individual in need ofweight management is an individual who is obese. To ine whether an individual is overweight or obese one can determine a body weight, a body mass index (BMI), a waist circumference or a body fat percentage ofthe individual to determine ifthe individual meets a body weight old, a BMI threshold, a waist circumference threshold or a body fat percentage threshold.

Determination ofbody weight can be through the use ofa visual estimation ofbody weight, the use ofa weight measuring device, such as an electronic weight scale or a mechanical beam scale. In some ments, an individual in need ofweight management is an adult male with a body weight greater than about 90 kg, greater than about 100 kg, or greater than about 110 kg. In some embodiments, an dual in need ofweight management is an adult female with a body weight greater than about 80 kg, greater than about 90 kg, or greater than about 100 kg. In some embodiments, the individual is prepubertal and has a body weight greater than about 30 kg, greater than about 40 kg, or greater than about 50 kg.

The healthy range ofBMI, and other measures ofwhether one is overweight or obese, can also be dependent on genetic or racial differences. For e, since Asian populations develop negative health consequences at a lower BMI than [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm Caucasians, some nations have ned obesity for their populations. For example, in Japan any BMI greater than 25 is defined as obese and in China any BMI greater than 28 is defined as obese. Similarly, different old values for body weight, waist circumference or body fat percentage can be used for different populations ofindividuals.

The WHO recommends that countries should use all ries for reporting purposes with a view to facilitating ational comparisons.

Determination ofBMI can be through the use of a visual estimation of BMI, the use ofa height ing device such as a stadiometer or a height rod and the use ofa weight measuring device, such as an electronic weight scale or a mechanical beam scale. In some embodiments, the individual in need ofweight management is an adult with a BMI ofgreater than about 25 kg/m2, greater than about 26 kg/m2, greater than about 27 kg/m2, greater than about 28 kg/m2, greater than about 29 kg/m2, greater than about 30 kg/m2, greater than about 31 kg/m2, greater than about 32 d kg/m2, greater than about 33 kg/m2, greater than about 34 kg/m2, greater than about 35 kg/m2, greater than about 36 kg/m2, greater than about 37 kg/m2, greater than about 38 kg/m2, greater than about 39 kg/m2, or greater than about 40 kg/m2. In some embodiments, the dual is prepubertal with a BMI ofgreater than about 20 kg/m2, greater than about 21 kg/m2, greater than about 22 kg/m2, greater than about 23 kg/m2, greater than about 24 kg/m2, greater than about 25 kg/m2, greater than about 26 kg/m2, greater than about 27 kg/m2, greater than about 28 kg/m2, greater than about 29 kg/m2, greater than about 30 kg/m2, greater than about 31 kg/m2, greater than about 32 kg/m2, greater than about 33 kg/m2, greater than about 34 kg/m2, or greater than about 35 kg/m2.

Determination ofwaist ference can be through the use ofa visual estimation ofwaist circumference or the use ofa waist circumference measuring device such as a tape measure.

Determinations ofthe healthy range ofwaist circumference and percentage body fat in an individual are dependent on gender. For e, women typically have smaller waist circumferences than men and so the waist circumference threshold for being overweight or obese is lower for a woman. In addition, women lly have a greater percentage ofbody fat than men and so the percentage body fat threshold for being overweight or obese for a woman is higher than for a man. Further, the healthy range of BMI and other measures ofwhether one is overweight or obese can be dependent on age.

[Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm For e, the body weight threshold for considering whether one is overweight or obese is lower for a child (prepubertal individual) than for an adult.

In some embodiments, the individual in need ofweight management is an adult male with a waist circumference ter than about 100 cm, greater than about 110 cm, or greater than about 120 cm, or an adult female with a waist circumference of r than about 80 cm, greater than about 90 cm, or greater than about 100 cm. In some embodiments, the individual is prepubertal with a waist ference ofabout of greater than about 60 cm, greater than about 70 cm, or greater than about 80 cm.

Determination ofbody fat percentage can be through the use ofa visual estimation ofbody fat tage or the use ofa body fat percentage measuring device such as bioelectric impedance, computed tomography, magnetic resonance imaging, near infrared interactance, dual energy X ray absorptiometry, use ofultrasonic waves, use of body e density measurement, use fold methods, or use ofheight and circumference methods. In some embodiments, the individual in need ofweight management is an adult male with a body fat percentage of greater than about 25%, greater than about 30%, or greater than about 35%, or an adult female with a body fat percentage ter than about 30%, greater than about 35%, or greater than about 40%.

In some embodiments, the individual is prepubertal with a body fat percentage of greater than about 30%, greater than about 35%, or r than about 40%.

In some ments, the individual has an initial body mass index 2: 25 kg/m2.

In some embodiments, the individual has an initial body mass index 2: 25 kg/m2 and at least one weight related comorbid condition. In some embodiments, the weight related comorbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance and sleep apnea. In some embodiments, the weight related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 diabetes.

In some embodiments, the dual has an initial body mass index 2: 27 kg/m2. In some embodiments, the individual has an l body mass index 2: 27 kg/m2 and at least one weight related comorbid condition. In some embodiments, the weight related comorbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance and sleep apnea. In some embodiments, the weight related comorbid condition is selected from: hypertension, idemia, and type 2 diabetes. ation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm ation] kjm ed set by kjm In some embodiments, the individual has type 2 diabetes.

In some embodiments, the individual has impaired fasting glucose. In some embodiments, the individual has a fasting glucose ofless than about 100 mg/dL. In some embodiments, the individual has a fasting glucose ofless than about 70 mg/dL. In some embodiments, the individual has a fasting glucose ofless than about 65 mg/dL. In some embodiments, the individual has a fasting glucose ofless than about 50 mg/dL.

In some ments, the dual has an initial body mass index 2: 30 kg/m2. In some ments, the individual has an initial body mass index 2: 30 kg/m2 and at least one weight related comorbid condition. In some ments, the weight related comorbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, e intolerance and sleep apnea. In some embodiments, the weight related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 diabetes.

In some embodiments, the first time period ofadministration is from about 2 weeks to about 6 months. In some embodiments, the first time period ofadministration is from about 4 weeks to about 4 months. In some embodiments, the first time period of administration is about 12 weeks.

In some embodiments, the threshold effect comprises a se in an assessment ofweight.

In some embodiments, a decrease in an assessment ofweight ses weight loss of at least about 1%.

In some embodiments, a decrease in an assessment ofweight comprises weight loss of at least about 1 % and said first time period ofadministration is about 2 weeks. In some embodiments, a decrease in an assessment ofweight ses weight loss ofat least about 1.5% and said first time period ofadministration is about 2 weeks.

In some embodiments, a decrease in an assessment ofweight comprises weight loss of at least about 2%.

In some embodiments, a decrease in an assessment ofweight comprises weight loss of at least about 2% and said first time period ofadministration is about 4 weeks. In some embodiments, a decrease in an assessment ofweight comprises weight loss ofat least about 2.5% and said first time period ofadministration is about 4 weeks.

In some embodiments, a decrease in an assessment ofweight comprises weight loss of at least about 3%.

[Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm In some ments, a decrease in an assessment ofweight comprises weight loss of at least about 3% and said first time period ofadministration is about 8 weeks. In some embodiments, a decrease in an assessment ht comprises weight loss ofat least about 3.5% and said first time period ofadministration is about 8 weeks.

In some embodiments, a decrease in an assessment ofweight comprises weight loss ofat least about 3.9% and said first time period ofadministration is about 8 weeks.

In some embodiments, a decrease in an assessment ht comprises weight loss of at least about 4%.

In some embodiments, a decrease in an assessment ofweight comprises weight loss of at least about 4% and said first time period ofadministration is about 12 weeks. In some embodiments, a decrease in an assessment ht comprises weight loss ofat least about 4.5% and said first time period ofadministration is about 12 weeks.

In some embodiments, a decrease in an assessment ofweight comprises weight loss ofat least about 4.6% and said first time period ofadministration is about 12 weeks.

In some embodiments, a decrease in an assessment ofweight comprises weight loss of at least about 5%.

In some embodiments, a decrease in an assessment ofweight comprises weight loss of at least about 5% and said first time period ofadministration is about 12 weeks.

In some embodiments, a decrease in an assessment ofweight ses weight loss of at least about 6%.

In some embodiments, a decrease in an assessment ht comprises weight loss of at least about 6% and said first time period ofadministration is about 12 weeks. In some ments, a decrease in an assessment ht comprises weight loss ofat least about 6% and said first time period ofadministration is about 24 weeks.

In some embodiments, a decrease in an assessment ofweight comprises weight loss ofat least about 6.1 % and said first time period ofadministration is about 24 weeks. In some ments, a decrease in an assessment ofweight comprises weight loss ofat least about 5.9% and said first time period ofadministration is about 24 weeks.

In some embodiments, a decrease in an assessment ofweight ses weight loss of at least about 9%.

In some embodiments, a decrease in an assessment ofweight comprises weight loss of at least about 8.5% and said first time period ofadministration is about 24 [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm ed set by kjm weeks. In some embodiments, a decrease in an assessment ofweight ses weight loss ofat least about 9% and said first time period ofadministration is about 24 weeks.

In some embodiments, a decrease in an assessment ofweight comprises a decrease in BMI.

In some embodiments, a decrease in an ment ofweight ses a decrease in percent body fat.

In some embodiments, a decrease in an assessment ofweight comprises a decrease in waist circumference.

] In some embodiments, achievement of a threshold effect after the first time period ofadministration correlates with a likelihood ofthe individual achieving one or more additional beneficial effects after a second time period ofadministration.

In some embodiments, the second time period ofadministration is about one year.

] In some embodiments, the one or more additional beneficial effects comprises an additional decrease in an assessment ofweight.

In some embodiments, the one or more onal beneficial effects are chosen from a decrease in an ment ofweight, an improvement in cardiovascular indications and/or an improved glycemia.

In some embodiments, the one or more additional beneficial s comprise a decrease in an assessment ofweight. In some embodiments, the decrease in an assessment ofweight comprises weight loss.

In some embodiments, the weight loss in an individual without type 2 diabetes is n about 10 and 12 kg. In some embodiments, the weight loss in an dual without type 2 diabetes is about 10 kg. In some embodiments, the weight loss in an individual without type 2 diabetes is about 10.5 kg.

In some embodiments, the weight loss in an individual with type 2 diabetes is at least about 5 kg. In some embodiments, the weight loss in an individual with type 2 diabetes is between about 5 and 10 kg. In some embodiments, the weight loss in an individual with type 2 diabetes is about 9 kg.

In some embodiments, the weight loss in an dual with baseline impaired fasting glucose is at least about 5 kg. In some embodiments, the weight loss in an individual with baseline impaired fasting glucose is at least about 10 kg. In some embodiments, the weight loss in an individual with ne impaired fasting glucose is [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm between about 10 and 15 kg. In some embodiments, the weight loss in an individual with baseline impaired fasting glucose is about 11 kg.

In some embodiments, the decrease in an ment ofweight comprises a decrease in , a se in food cravings, or an increase in intermeal interval.

In some embodiments, the one or more additional beneficial effects comprise an improvement in one or more cardiovascular tions. In some embodiments, the improvement in one or more cardiovascular tions comprises one or more ofa reduction in systolic and diastolic blood pressure (SBP and DBP, respectively), a decrease in heart rate, a decrease in total cholesterol, a decrease in LDL cholesterol, a decrease in HDL cholesterol, and/or a decrease in triglyceride levels.

In some embodiments, the one or more additional beneficial effects comprise a reduction in SBP.

In some embodiments, the reduction in SBP in an individual without type 2 diabetes is at least about 2 mmHg. In some embodiments, the reduction in SBP in an individual without type 2 diabetes is between 2 and 5 mmHg. In some embodiments, the reduction in SBP in an dual without type 2 diabetes is about 3 mmHg. In some ments, the reduction in SBP in an individual without type 2 diabetes is about 3.5 mmHg.

In some embodiments, the reduction in SBP in an individual with type 2 diabetes is at least about 2 mmHg. In some embodiments, the ion in SBP in an individual with type 2 diabetes is between about 2 and 5 mmHg. In some embodiments, the reduction in SBP in an dual with type 2 diabetes is about 2.5 mmHg. In some embodiments, the reduction in SBP in an individual with type 2 diabetes is about 3 mmHg.

In some embodiments, the reduction in SBP in an dual with baseline impaired fasting glucose is at least about 1 mmHg. In some ments, the reduction in SBP in an individual with baseline impaired fasting glucose is between about 1 and 5 mmHg. In some embodiments, the reduction in SBP in an individual with ne impaired fasting glucose is about 1.5 mmHg. In some embodiments, the reduction in SBP in an individual with baseline ed g glucose is about 2 mmHg.

In some embodiments, the one or more additional cial effects comprise a reduction in DBP.

In some embodiments, the reduction in DBP in an individual without type 2 diabetes is at least about 1 mmHg. In some embodiments, the reduction in DBP in an ation] kjm None set by kjm [Annotation] kjm ionNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm individual without type 2 diabetes is at least n about 1 and 5 mmHg. In some embodiments, the reduction in DBP in an individual t type 2 diabetes is about 2 mmHg. In some embodiments, the ion in DBP in an individual without type 2 diabetes is about 2.5 mmHg. In some embodiments, the reduction in DBP in an individual without type 2 diabetes is about 3 mmHg.

In some embodiments, the reduction in DBP in an individual with type 2 diabetes is at least about 1 mmHg. In some embodiments, the reduction in DBP in an individual with type 2 diabetes is between about 1 and 5 mmHg. In some embodiments, the reduction in DBP in an individual with type 2 diabetes is about 1.5 mmHg. In some embodiments, the reduction in DBP in an individual with type 2 es is about 2 mmHg.

] In some ments, the reduction in DBP in an individual with baseline impaired fasting glucose is at least about 1 mmHg. In some embodiments, the reduction in DBP in an individual with baseline impaired fasting glucose is between about 1 and 5 mmHg. In some embodiments, the reduction in DBP in an individual with baseline impaired fasting e is about 1.5 mmHg. In some embodiments, the reduction in DBP in an individual with baseline ed fasting glucose is about 2 mmHg.

In some embodiments, the one or more additional beneficial effects comprise a reduction in heart rate.

In some embodiments, the reduction in heart rate in an individual without type 2 diabetes is at least about 2 BPM. In some embodiments, the reduction in heart rate in an individual without type 2 diabetes is between about 2 and 5 BPM. In some embodiments, the reduction in heart rate in an individual without type 2 diabetes is about 2 BPM. In some embodiments, the reduction in heart rate in an individual without type 2 diabetes is about 2.5 BPM. In some embodiments, the reduction in heart rate in an individual without type 2 diabetes is about 3 BPM.

] In some embodiments, the reduction in heart rate in an individual with type 2 diabetes is at least about 2 BPM. In some embodiments, the reduction in heart rate in an individual with type 2 diabetes is between about 2 and 5 BPM. In some embodiments, the reduction in heart rate in an individual with type 2 diabetes is about 3 BPM. In some embodiments, the reduction in heart rate in an individual with type 2 diabetes is about 3.5 BPM.

In some embodiments, the reduction in heart rate in an individual with baseline impaired fasting glucose is at least about 2 BPM. In some embodiments, the ation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm ed set by kjm reduction in heart rate in an individual with baseline impaired fasting glucose is between about 2 and 5 BPM. In some embodiments, the reduction in heart rate in an individual with baseline impaired fasting glucose is about 3.5 BPM. In some embodiments, the reduction in heart rate in an dual with baseline impaired fasting glucose is about 4 BPM.

In some embodiments, the improvement in glycemia comprises a decrease in total cholesterol level.

In some embodiments, the decrease in total cholesterol level in patients without type 2 diabetes is at least about 1 mg/dL. In some embodiments, the decrease in total cholesterol level in patients without type 2 diabetes is at least about 1.5 mg/dL. In some embodiments, the decrease in total cholesterol level in ts without type 2 diabetes is between about 1.5 and 2 mg/dL. In some embodiments, the decrease in total cholesterol level in patients without type 2 diabetes is about 1.7 mg/dL.

In some embodiments, the decrease in total cholesterol level in patients with type 2 diabetes is at least about 0.5 mg/dL. In some embodiments, the decrease in total cholesterol level in patients with type 2 diabetes is between about 0.5 and 1 mg/dL. In some embodiments, the decrease in total cholesterol level in patients with type 2 diabetes is about O. 7 mg/dL.

In some embodiments, the decrease in total cholesterol level in patients with baseline impaired fasting glucose is at least about 2 mg/dL. In some embodiments, the decrease in total cholesterol level in patients with baseline ed fasting glucose is between about 2 and 3 mg/dL. In some embodiments, the decrease in total terol level in patients with baseline impaired fasting glucose is about 2.3 mg/dL.

In some ments, the improvement in glycemia comprises a decrease in LDL cholesterol level.

In some embodiments, the decrease in LDL cholesterol level in patients t type 2 diabetes is at least about 1 mg/dL. In some ments, the se in LDL cholesterol level in patients without type 2 es is between about 1 and 2 mg/dL.

In some embodiments, the decrease in LDL terol level in patients without type 2 diabetes is about 1.1 mg/dL.

In some embodiments, the decrease in LDL cholesterol level in patients with type 2 diabetes is at least about 1 mg/dL. In some embodiments, the se in LDL cholesterol level in patients with type 2 es is between about 1 and 1.5 mg/dL. In [Annotation] kjm None set by kjm [Annotation] kjm ionNone set by kjm ation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm some ments, the decrease in LDL cholesterol level in patients with type 2 diabetes is about 1.4 mg/dL.

In some embodiments, the decrease in LDL cholesterol level in patients with baseline impaired fasting glucose is at least about 2 mg/dL. In some embodiments, the decrease in LDL cholesterol level in patients with baseline impaired fasting glucose is n about 2 and 3 mg/dL. In some embodiments, the decrease in LDL cholesterol level in patients with baseline ed g glucose is about 2.5 mg/dL.

In some embodiments, the improvement in glycemia comprises a decrease in HDL terol level.

In some embodiments, the decrease in HDL cholesterol level in ts without type 2 diabetes is at least about 4 mg/dL. In some ments, the se in HDL cholesterol level in patients without type 2 diabetes is between about 3 and 6 mg/dL.

In some embodiments, the decrease in HDL terol level in patients without type 2 diabetes is about 4.6 mg/dL.

In some embodiments, the decrease in HDL cholesterol level in patients with type 2 diabetes is at least about 5 mg/dL. In some embodiments, the decrease in HDL cholesterol level in patients with type 2 diabetes is at least about 7 mg/dL. In some embodiments, the decrease in HDL cholesterol level in patients with type 2 diabetes is between about 7 and 10 mg/dL. In some ments, the decrease in HDL cholesterol level in patients with type 2 diabetes is about 8.8 mg/dL.

In some embodiments, the decrease in HDL cholesterol level in patients with ne impaired fasting e is at least about 2 mg/dL. In some embodiments, the decrease in HDL cholesterol level in ts with baseline impaired fasting glucose is between about 2 and 3 mg/dL. In some embodiments, the decrease in HDL cholesterol level in patients with baseline impaired fasting glucose is about 2.1 mg/dL.

In some embodiments, the one or more additional beneficial effects comprise an improvement in glycemia. In some embodiments, the improvement in glycemia comprises a reduction in fasting plasma glucose and/or a reduction in glycated hemoglobin (AlC) levels.

In some embodiments, the improvement in glycemia comprises a reduction in fasting plasma glucose.

In some embodiments, the reduction in fasting plasma glucose in patients without type 2 diabetes is at least about 1 mg/dL. In some embodiments, the reduction in [Annotation] kjm None set by kjm [Annotation] kjm ionNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm fasting plasma glucose in patients t type 2 diabetes is at least about 1.5 mg/dL. In some embodiments, the reduction in g plasma e in patients without type 2 diabetes is between about 1 and 4 mg/dL. In some embodiments, the reduction in fasting plasma glucose in patients without type 2 diabetes is about 2.2 mg/dL.

In some embodiments, the reduction in fasting plasma glucose in patients with type 2 diabetes is at least about 10 mg/dL. In some embodiments, the reduction in fasting plasma e in patients with type 2 diabetes is n about 10 and 40 mg/dL.

In some embodiments, the reduction in fasting plasma glucose in ts with type 2 diabetes is about 25 mg/dL. In some ments, the reduction in fasting plasma glucose in patients with type 2 diabetes is about 30 mg/dL.

In some embodiments, the reduction in fasting plasma glucose in patients with baseline impaired fasting glucose is at least about 5 mg/dL. In some embodiments, the reduction in fasting plasma glucose in patients with baseline impaired g glucose is between about 5 and 10 mg/dL. In some embodiments, the reduction in g plasma glucose in patients with baseline impaired fasting glucose is about 7 mg/dL. In some embodiments, the reduction in fasting plasma glucose in patients with baseline impaired fasting glucose is about 8 mg/dL.

In some embodiments, the improvement in ia comprises a reduction in glycated hemoglobin (AlC) levels.

] In some embodiments, the reduction in glycated hemoglobin (AIC) level in patients without type 2 diabetes is at least about 0.1 %. In some embodiments, the reduction in glycated hemoglobin (AlC) level in patients t type 2 diabetes is between about 0.1 and 0.2%. In some embodiments, the reduction in glycated hemoglobin (AIC) level in patients without type 2 es is about 0.15%. In some embodiments, the reduction in glycated hemoglobin (AlC) level in patients without type 2 diabetes is about 0.18%.

In some embodiments, the reduction in glycated hemoglobin (AIC) level in patients with type 2 diabetes is at least about 0.5%. In some embodiments, the reduction in glycated hemoglobin (AlC) level in patients with type 2 diabetes is between about 1 and 2%. In some embodiments, the reduction in glycated hemoglobin (AlC) level in patients with type 2 diabetes is about 1.2%.

In some embodiments, the reduction in glycated hemoglobin (AIC) level in patients with baseline impaired g glucose is at least about 0.05%. In some [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm ation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm embodiments, the reduction in glycated hemoglobin (AlC) level in patients with baseline impaired fasting glucose is between about 0.05 and 0.2%. In some embodiments, the reduction in glycated hemoglobin level (AlC) in patients with baseline ed g glucose is about 0.1 %.

In some embodiments, the improvement in glycemia comprises a decrease in triglyceride levels.

In some embodiments, the decrease in triglyceride level in patients without type 2 diabetes is at least about 5 mg/dL. In some embodiments, the decrease in triglyceride level in patients without type 2 diabetes is between about 5 and 20 mg/dL. In some embodiments, the decrease in ceride level in patients without type 2 diabetes is about 14 mg/dL. In some embodiments, the decrease in triglyceride level in patients without type 2 diabetes is about 14.5 mg/dL.

In some embodiments, the decrease in triglyceride level in patients with type 2 diabetes is at least about 10 mg/dL. In some embodiments, the decrease in triglyceride level in patients with type 2 diabetes is between about 10 and 20 mg/dL. In some embodiments, the decrease in ceride level in patients with type 2 diabetes is about 17 mg/dL. In some embodiments, the decrease in triglyceride level in patients with type 2 diabetes is about 17.8 mg/dL.

In some embodiments, the decrease in triglyceride level in patients with baseline impaired fasting glucose is at least about 5 mg/dL. In some embodiments, the decrease in triglyceride level in patients with ne impaired fasting glucose is between about 5 and 20 mg/dL. In some embodiments, the decrease in triglyceride level in patients with baseline impaired fasting glucose is about 15 mg/dL.

Also provided is a method for weight ment in an individual in need thereof, comprising the steps of: administering a therapeutically ive amount of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or e fto an individual, wherein said individual has previously been ined to be a der according to any ofthe methods described herein or selected for treatment according to any ofthe s described herein.

Also ed is a method for weight management in an individual in need thereof, comprising the steps of: [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm administering a therapeutically effective amount of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically able salt, solvate or hydrate thereofto an individual, wherein said individual has previously been determined to be a responder according to a method comprising the steps of: measuring an individual'sresponsiveness to chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof after a first time period ofadministration of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto the individual, wherein ifthe individual has achieved a threshold effect after said first time period ofadministration, the individual is a responder.

Also provided is a method for weight ment in an individual in need thereof, comprising the steps of: administering a therapeutically effective amount of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto an individual, wherein said individual has previously been ed for treatment ing to a method comprising the steps of: measuring an individual'sresponsiveness to (R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate f after a first time period ofadministration of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, e or hydrate thereofto the individual; and ing the individual for treatment with (R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofifthe individual has achieved a threshold effect after said first time period of administration.

Also provided is a method for weight management in an individual in need thereof, comprising the steps of: administering to the individual a therapeutically ive amount of(R)chloro- yl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm ionNone set by kjm [Annotation] kjm Unmarked set by kjm determining r the individual is a responder or is selected for treatment according to any ofthe methods described herein; and continuing administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro- IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate fifthe individual is identified as a responder, or modifying the administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro-IH- 3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto the individual ifthe individual is not identified as a responder.

Also provided is a method for weight management in an individual in need thereof, comprising the steps of: administering to the individual a therapeutically effective amount of(R)chloro- 1-methyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; determining r the individual is a responder ing to a method comprising the steps of: measuring an individual'sresponsiveness to (R)chloromethyl- 2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof after a first time period ofadministration of(R) chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof to the individual, wherein ifthe dual has achieved a old effect after said first time period ofadministration, the individual is a responder; and continuing administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro- IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate fifthe dual is identified as a responder, or modifying the administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro-IH- 3-benzazepine or a pharmaceutically able salt, solvate or hydrate thereofto the individual ifthe individual is not identified as a responder.

Also provided is a method for assisting weight management in an individual in need f, comprising the steps of: measuring r wherein said individual is a responder according to any ofthe methods described herein or selected for treatment according to any ofthe methods described herein, [Annotation] kjm None set by kjm ation] kjm ionNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm wherein a measurement that the individual is a responder or is selected for treatment indicates that the individual is suitable for prescription ofa therapeutically ive amount of(R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Also provided is a method for assisting weight management in an individual in need thereof, comprising the steps of: measuring the individual'sresponsiveness to (R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof after a first time period ofadministration of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically able salt, solvate or e thereofto the individual, wherein a measurement that the individual has ed a threshold effect after said first time period ofadministration indicates that the individual is a responder and is suitable for prescription of a a therapeutically effective amount of(R)chloromethyl- 2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically able salt, solvate or hydrate thereofto an individual.

Also provided is a method for assisting weight management in an individual in need thereof, sing the steps of: measuring an individual'sresponsiveness to (R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof after a first time period ofadministration of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto the individual; n a measurement that the individual has achieved a old effect after said first time period ofadministration of(R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine or a ceutically acceptable salt, solvate or hydrate thereofindicates that the individual is le for selection for prescription ofa therapeutically effective amount of (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto an individual.

Also ed is a method for assisting weight ment in an individual in need thereof, comprising the steps of: measuring whether the individual is a responder or is selected for treatment according to any ofthe methods described herein, ation] kjm None set by kjm [Annotation] kjm ionNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm n a measurement that the individual is a responder indicates that the individual is le for continuing prescription ofa therapeutically effective amount of (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; and wherein a measurement that the individual is not a responder indicates that the individual is suitable for a ed iption ofthe (R)chloromethyl-2,3,4,5- ydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate.

Also provided is a method for assisting weight management in an individual in need thereof, comprising the steps of: measuring whether the dual is a responder according to a method comprising the steps of: measuring an individual'sresponsiveness to (R)chloromethyl- 2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or e thereof after a first time period ofadministration of(R) chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof to the individual, wherein ifthe individual has achieved a threshold effect after said first time period ofadministration, the individual is a responder; and wherein a measurement that the individual is a responder tes that the individual is suitable for a continuing prescription ofthe (R)chloromethyl-2,3,4,5- ydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate, or wherein a measurement that the individual is not a responder indicates that the individual is le for a ed prescription ofthe (R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In some embodiments, modifying the administration ofthe (R)chloro methyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises increasing the dose and/or frequency of administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In some embodiments, modifying the administration ofthe (R)chloro methyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically able salt, solvate or hydrate thereof comprises prescribing or administering a weight loss compound [Annotation] kjm None set by kjm [Annotation] kjm ionNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm or procedure to the individual to be used in combination with the (R)chloromethyl- 2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Combinations of (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine with other agents, including without limitation, phentermine, and uses of such combinations in therapy are described in , which is incorporated herein by nce in its entirety. In some embodiments, the weight loss compound is selected from amphetamine, caffeine, bromocriptine, ephedrine, pseudoephedrine, phenylpropanolamine, diethylpropion, benzphetamine, rimonabant, mazindol, surinabant, orlistat, stat, sibutramine, bupropion, citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, milnacipran, mirtazapine, venlafaxine, desvenlafaxine, topiramate, zonisamide, metformin, ide, pramlintide, utide, obinepitide, naltrexone, phentermine, phendimetrazine, insulin, dexfenfluramine, fenfluramine, leptin, naltrexone, and pharmaceutically able salts and combinations thereof. In some embodiments, the weight loss compound is phentermine.

In some embodiments, modifying the administration ofthe (R)chloro methyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or e thereof comprises prescribing or administering to the individual a weight loss compound chosen from cannabinoid CB 1 receptor antagonists, lipase inhibitors, ine reuptake inhibitors, anticonvulsants, glucose sensitizers, incretin mimetics, amylin analogs, GLP-1 analogs, Y receptor peptides, 5HT2C serotonin receptor agonists, opioid receptor nists, appetite suppressants, anorectics, and hormones.

In some embodiments, modifying the administration ofthe (R)chloro methyl-2,3,4,5-tetrahydro-IHbenzazepine or a ceutically acceptable salt, solvate or hydrate thereof comprises prescribing or administering to the individual a weight loss compound chosen from amphetamine, caffeine, bromocriptine, ephedrine, pseudoephedrine, phenylpropanolamine, diethylpropion, benzphetamine, rimonabant, mazindol, surinabant, orlistat, cetilistat, sibutramine, ion, citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, milnacipran, apine, venlafaxine, desvenlafaxine, mate, mide, min, exenatide, ntide, liraglutide, obinepitide, naltrexone, phentermine, metrazine, insulin, dexfenfluramine, fenfluramine, leptin, naltrexone, and pharmaceutically acceptable salts and combinations thereof.

[Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm ed set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm ed set by kjm In some embodiments, modifying the administration ofthe (R)chloro methyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises discontinuing the prescribing or administering ofthe (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In some ments, the procedure comprises a al weight loss procedure.

In some embodiments, the methods for weight management further comprise prescribing and/or administering a reduced-calorie diet.

In some embodiments, the methods for weight management r comprise prescribing and/or administering a program ofregular exercise.

In some ments, the methods for weight management further comprise ibing and/or administering phentermine to the individual.

In some embodiments, weight ment comprises weight loss.

In some embodiments, weight ment comprises maintenance of weight loss.

In some embodiments, the terms "(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof'and -chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine, and pharmaceutically acceptable salts, solvates, and hydrates thereof'as used herein encompass any one ofthe following salts, or a Markush group comprising any combination ofthe following salts: (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hydrochloride salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hydrobromide salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hydroiodide salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine maleate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine fumarate salt; and (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hemifumarate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine orotate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine di-acetamidobenzoate salt-cocrystal; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine trans-cinnamate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine heminapadisilate salt; ation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine (±)-mandelate salt; chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hemipamoate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine (IS)-(+) ate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hemi-L-malate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine L-glutamate salt; (R)chloromethyl-2,3 ,4,5-tetrahydro-1Hbenzazepine L-aspartate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hemimucate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine pyroglutamate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine glucuronate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine di-camphorate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine bisulfate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hemisulfate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine mesylate salt; (R)chloromethyl-2,3 ,4,5-tetrahydro-1Hbenzazepine hydrobromide salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine nitrate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine sesqui-oxalate saltcocrystal (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine adipate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine te salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hemimalonate salt; chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine glycolate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hemi-edisylate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine phosphate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine citrate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hemi-oxalate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine ate salt; and (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine oxoglutarate salt; and pharmaceutically able solvates and es thereof.

In some embodiments, the terms "(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof'and "(R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine, and pharmaceutically acceptable salts, solvates, and hydrates thereof'as used herein [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm ed set by kjm encompass any one ofthe following salts, or a Markush group comprising any ation ofthe following salts: (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hydrochloride salt; (R)chloromethyl-2,3 ,4,5-tetrahydro-1Hbenzazepine hloride salt hemihydrate; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hydrochloride salt hydrate; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hydrobromide salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hydroiodide salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine maleate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine fumarate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine marate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine orotate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine orotate salt hydrate; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine di acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine cinnamate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine heminapadisilate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine heminapadisilate salt solvate 1; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine heminapadisilate salt solvate 2; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine (±)-mandelate salt hydrate; (R)chloromethyl-2,3 ,4,5-tetrahydro-1Hbenzazepine moate salt hydrate; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine (IS)-(+) camsylate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hemi-L-malate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine L-glutamate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine L-aspartate salt; chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hemimucate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine pyroglutamate salt; [Annotation] kjm None set by kjm [Annotation] kjm ionNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine glucuronate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine di-camphorate salt solvate; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine bisulfate salt; (R)chloromethyl-2,3 etrahydro-1Hbenzazepine hemisulfate salt hydrate; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine te salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hydrobromide salt hemihydrate; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine nitrate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine sesqui-oxalate saltcocrystal (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine adipate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine malonate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hemimalonate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine glycolate salt; chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine disylate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine phosphate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine citrate salt hemihydrate; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hemi-oxalate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine succinate salt; (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine oxoglutarate salt; and (R)chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine oxoglutarate salt solvate.

In some embodiments, the (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof is (R) chloromethyl-2,3,4,5-tetrahydro-IHbenzazepine hydrochloride or a solvate or hydrate thereof.

In some ments, the (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine or a pharmaceutically acceptable salt, e or hydrate thereof is (R) chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride hemihydrate.

[Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm It is understood that when the phrase "pharmaceutically able salts, es and hydrates" or the phrase "pharmaceutically acceptable salt, solvate or hydrate" is used when referring to compounds described herein, it embraces ceutically acceptable solvates and/or hydrates ofthe compounds, ceutically acceptable salts ofthe compounds, as well as pharmaceutically acceptable solvates and/or hydrates ofpharmaceutically acceptable salts ofthe compounds. It is also understood that when the phrase "pharmaceutically able solvates and hydrates" or the phrase "pharmaceutically acceptable solvate or hydrate" is used when referring to compounds described herein that are salts, it embraces pharmaceutically acceptable solvates and/or hydrates ofsuch salts.

It will be apparent to those skilled in the art that the dosage forms described herein may se, as the active component, either a compound described herein or a pharmaceutically acceptable salt or as a solvate or hydrate thereof. Moreover, various hydrates and solvates ofthe compounds described herein and their salts will find use as ediates in the manufacture ofpharmaceutical compositions. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of K.J. Guillory, "Generation ofPolymorphs, Hydrates, Solvates, and Amorphous Solids," in: Polymorphism in Pharmaceutical Solids, ed. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999. Accordingly, one aspect ofthe t disclosure pertains to methods ofadministering hydrates and solvates ofcompounds described herein and/or their pharmaceutical able salts, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, frared spectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration, high resolution X-ray diffraction, and the like. There are several commercial entities that provide quick and efficient services for identifying solvates and es on a routine basis. Example companies offering these es include Wilmington PharmaTech (Wilmington, DE), Avantium Technologies (Amsterdam) and Aptuit wich, CT).

The t disclosure includes all es ofatoms ing in the present salts and crystalline forms thereof. Isotopes e those atoms having the same atomic number but different mass numbers. One aspect ofthe present invention includes every combination ofone or more atoms in the present salts and crystalline forms thereof that is replaced with an atom having the same atomic number but a different mass ation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm ation] kjm ed set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm ed set by kjm number. One such example is the replacement ofan atom that is the most naturally abundant isotope, such as 1H or 12C, found in one the t salts and crystalline forms thereof, with a different atom that is not the most naturally abundant isotope, such as 2H or 3H cing 1H), or 11 C, 13C, or 14C (replacing 12C). A salt wherein such a replacement has taken place is commonly referred to as being ically-labeled.

Isotopic-labeling ofthe present salts and crystalline forms thereof can be accomplished using any one ofa y ofdifferent synthetic methods know to those ofordinary skill in the art and they are readily credited with understanding the tic methods and available reagents needed to conduct such isotopic-labeling. By way of l example, and without limitation, isotopes ofhydrogen include 2H (deuterium) and 3H (tritium).

Isotopes on include 11 C, 13C, and 14C. Isotopes ofnitrogen include 13N and 15N.

Isotopes ofoxygen include 150, 170, and 18C. An isotope offluorine includes 18F. An isotope ofsulfur includes 35S. An e ofchlorine includes 36Cl. Isotopes ofbromine e 75Br, 76Br, 77Br, and 82Br. Isotopes ofiodine include 12 1241, 125 I, \ and 131 I.

Another aspect ofthe present invention includes compositions, such as, those prepared during synthesis, preformulation, and the like, and pharmaceutical itions, such as, those prepared with the intent ofusing in a mammal for the treatment ofone or more of the disorders described herein, sing one or more ofthe present salts and crystalline forms thereof, wherein the naturally occurring distribution ofthe isotopes in the composition is perturbed. Another aspect ofthe present invention includes compositions and pharmaceutical compositions comprising salts and crystalline forms thereof as described herein wherein the salt is enriched at one or more positions with an isotope other than the most naturally nt isotope. Methods are readily ble to measure such isotope perturbations or enrichments, such as, mass spectrometry, and for isotopes that are radio-isotopes additional methods are available, such as, radio-detectors used in connection with HPLC or GC.

Also provided is a compound for use in a method for decreasing food intake in an individual in need thereof, said method comprising the steps of: administering a therapeutically effective amount of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto an individual, wherein said individual has previously been determined to be a responder or selected for treatment according to any ofthe methods described herein; and [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm ed set by kjm wherein said compound is (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Also provided is a nd for use in a method for decreasing food intake in an individual in need thereof, said method comprising the steps of: administering to the individual a therapeutically effective amount of(R)chloro- 1-methyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; determining whether the individual is a responder or is selected for ent according to any ofthe methods described herein and continuing stration ofthe (R)chloromethyl-2,3,4,5-tetrahydro- IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate fifthe individual is identified as a responder, or modifying the stration ofthe (R)chloromethyl-2,3,4,5-tetrahydro-IH- 3-benzazepine or a pharmaceutically able salt, solvate or hydrate thereofto the individual ifthe individual is not identified as a responder; wherein said compound is (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Also provided is a nd for use in a method for inducing satiety in an dual in need thereof, said method comprising the steps of: administering a therapeutically ive amount of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto an dual, wherein said individual has previously been ined to be a responder or selected for treatment according to any ofthe methods described herein; and wherein said compound is (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Also provided is a compound for use in a method for inducing satiety in an individual in need thereof, said method comprising the steps of: administering to the individual a therapeutically effective amount of(R)chloro- 1-methyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; determining whether the individual is a responder or is selected for treatment ing to any ofthe methods described herein; and [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm continuing administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro- IH benzazepine or a pharmaceutically acceptable salt, e or hydrate thereofifthe individual is identified as a responder, or modifying the administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro-IH- 3-benzazepine or a pharmaceutically able salt, solvate or hydrate thereofto the individual ifthe individual is not identified as a der; wherein said compound is (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine or a pharmaceutically able salt, solvate or hydrate thereof.

Also provided is a nd for use in a method for the treatment of obesity in an individual in need thereof, said method comprising the steps of: administering a therapeutically ive amount of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto an individual, wherein said individual has previously been determined to be a responder or selected for treatment according to any ofthe methods described herein; and wherein said compound is (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Also provided is a compound for use in a method for the treatment of obesity in an dual in need thereof, said method comprising the steps of: administering to the individual a therapeutically ive amount of(R)chloro- 1-methyl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; determining r the individual is a responder or is selected for treatment according to any ofthe s described herein; and continuing administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro- IH benzazepine or a pharmaceutically acceptable salt, solvate or e thereofifthe individual is identified as a der, or modifying the administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro-IH- 3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto the individual ifthe individual is not identified as a responder; wherein said nd is (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine or a ceutically acceptable salt, solvate or hydrate thereof.

[Annotation] kjm None set by kjm [Annotation] kjm ionNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm Also provided is a compound for use in a method for the tion of obesity in an individual in need thereof, said method comprising the steps of: administering a eutically effective amount of(R)chloromethyl-2,3,4,5- tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto an individual, wherein said individual has previously been determined to a der or selected for ent ing to any ofthe methods described herein; and wherein said compound is (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine or a ceutically acceptable salt, solvate or e thereof.

Also provided is a compound for use in a method for the prevention of obesity in an individual in need thereof, said method comprising the steps of: administering to the individual a therapeutically effective amount of(R)chloro- yl-2,3,4,5-tetrahydro-IHbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate f; determining whether the dual is a responder or is selected for treatment according to any ofthe methods described herein; and continuing administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro- IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofifthe individual is identified as a responder, or modifying the administration ofthe (R)chloromethyl-2,3,4,5-tetrahydro-IH- 3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereofto the individual ifthe individual is not identified as a responder; wherein said compound is (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Also provided is a composition for use in a method ofweight management in an individual, comprising: a therapeutically effective amount of(R)chloromethyl-2,3,4,5-tetrahydro- enzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein the individual has previously been determined to be a responder according to any ofthe s described herein or selected for treatment according to any ofthe methods described herein.

Also provided is a kit for use in a method ofweight management in an individual, comprising: [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm a therapeutically effective amount of(R)chloromethyl-2,3,4,5-tetrahydro- IHbenzazepine or a pharmaceutically acceptable salt, e or hydrate f; and instructions indicating that the (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof is to be administered to an individual who has previously been determined to be a responder according to any ofthe s bed herein or selected for treatment according to any ofthe methods described herein.

In some embodiments, the kit further comprises phentermine.

In some embodiments, the (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to or less than 20 mg per day.

In some embodiments, the (R)chloromethyl-2,3,4,5-tetrahydro-IH benzazepine hydrochloride or a solvate or hydrate thereof is prescribed and/or administered to the individual in a dose equal to or less than 10 mg twice per day.

In some embodiments, the (R)chloromethyl-2,3,4,5-tetrahydro-IH epine or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered in a tablet suitable for oral administration.

Conventional excipients, such as binding agents, fillers, acceptable wetting agents, tabletting lubricants and disintegrants can be used in tablets and capsules for oral administration. Liquid preparations for oral administration can be in the form ofsolutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, the oral preparations can be in the form ofdry powder that can be reconstituted with water or r suitable liquid e before use. Additional ves such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants can be added to the liquid preparations. Parenteral dosage forms can be prepared by dissolving the compound in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an riate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for ing dosage forms. le pharmaceutically-acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The e and Practice ofPharmacy, 201h Edition, 2000, Lippincott Williams & Wilkins, (Editors: o et al.) While it is possible that, for use in the laxis or treatment, a compound can, in an alternative use, be administered as a raw or pure chemical, it is [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm preferable however to t the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.

Pharmaceutical formulations include those le for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation, insufflation or by a transdermal patch. Transdermal s dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with minimal degradation ofthe drug. Typically, transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a ble protective layer with a release liner. One ofordinary skill in the art will understand and appreciate the techniques riate for manufacturing a desired efficacious transdermal patch based upon the needs ofthe artisan.

] The compounds provided herein, together with a conventional adjuvant, carrier, or t, can thus be placed into the form ofpharmaceutical ations and unit dosages thereof and in such form may be ed as solids, such as tablets or filled capsules, or liquids, such as solutions, sions, emulsions, elixirs, gels or es filled with the same, all for oral use, in the form ofsuppositories for rectal administration; or in the form ofsterile injectable solutions for parenteral (including subcutaneous) use.

Such pharmaceutical compositions and unit dosage forms thereof can comprise conventional ients in conventional proportions, with or without additional active compounds or ples and such unit dosage forms may contain any suitable effective amount ofthe active ingredient commensurate with the intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition can be in the form of, for example, a , capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form ofa dosage unit containing a particular amount ofthe active ingredient. Examples ofsuch dosage units are capsules, tablets, powders, es or a suspension, with conventional additives such as lactose, mannitol, com starch or potato starch; with binders such as lline cellulose, cellulose derivatives, acacia, com starch or gelatins; with disintegrators such as com starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient may also be administered by injection as a composition wherein, for [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm ation] kjm Unmarked set by kjm example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable earner.

The dose when using the compounds provided herein can vary within wide limits and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity ofthe illness to be d, on the ion ofthe patient, on the compound employed, on whether an acute or chronic disease state is treated or prophylaxis conducted or on whether further active compounds are administered in addition to the compounds provided herein. Representative doses include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg.

Multiple doses may be administered during the day, especially when relatively large s are deemed to be needed, for example 2, 3 or 4 doses. Depending on the dual and as deemed appropriate from the healthcare provider it may be necessary to deviate upward or downward from the doses described herein.

The amount ofactive ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route nistration, the nature ofthe condition being treated and the age and condition ofthe patient and will ultimately be at the discretion ofthe attendant physician or ian. In general, one skilled in the art understands how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human. In some circumstances, these extrapolations may merely be based on the weight ofthe animal model in comparison to r, such as a mammal, preferably a human, r, more often, these extrapolations are not simply based on weights, but rather incorporate a variety offactors. Representative factors include the type, age, weight, sex, diet and medical condition ofthe t, the severity ofthe disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles ofthe ular compound employed, whether a drug delivery system is utilized, whether an acute or chronic disease state is being treated or prophylaxis conducted or whether further active nds are administered in addition to the compounds provided herein such as part ofa drug combination. The dosage regimen for treating a disease ion with the compounds and/or compositions provided herein is ation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm ation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm selected in accordance with a variety factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods disclosed .

The d dose may conveniently be presented in a single dose or as divided doses administered at riate intervals, for e, as two, three, four or more sub-doses per day. The sub-dose itselfmay be r d, e.g., into a number of discrete loosely spaced administrations. The daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4 part administrations. Ifappropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose ted.

The compounds provided herein can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the dosage forms may comprise, as the active component, either a compound provided herein or a pharmaceutically acceptable salt, solvate or hydrate of a compound provided herein.

Some embodiments include a method ofproducing a pharmaceutical composition for "combination-therapy" comprising ng at least one compound according to any ofthe compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable earner.

EXAMPLES Example 1 - Phase 3 Studies APD356-009 ("BLOOM") was a 104-week, placebo controlled study that assessed the safety and efficacy oflorcaserin 10 mg BID in overweight and obese patients, with concurrent behavior modification. The primary efficacy objective during Year 1 was to evaluate weight loss; the primary objective during Year 2 was to assess the y oflorcaserin to maintain body weight loss that was achieved during Year 1. At study start, each patient ed randomized, double blind treatment assignments for Year 1 and for Year 2 (all ts were given a new randomization number for Year 2 to assure that patients and study personnel remained blinded to ent assignments). All patients ed to placebo during Year 1 (50% ofrandomized population) remained on placebo in Year 2. Patients assigned to lorcaserin during Year 1 were randomly assigned [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm ation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm ed set by kjm to stay on lorcaserin during Year 2 (2/3 ofYear 1 lorcaserin patients) or to switch to placebo (1/3 ofYear 1 lorcaserin patients). Lorcaserin met the pre-specified Year 1 categorical and mean weight loss endpoints, and the Year 2 weight maintenance endpoint.

APD356-010 (BLOOM-DM) was a 52-week, placebo controlled study that evaluated the effect oftwo lorcaserin doses (10 mg BID and 10 mg QD) on categorical and total weight loss with rent behavior modification in 604 patients with type 2 diabetes mellitus managed with oral hypoglycemic . Randomization to the 10 mg once daily group was halted by protocol amendment in order to rate enrollment, resulting in final group sizes of253 bo), 95 (lorcaserin QD) and 256 (lorcaserin BID). Lorcaserin at both doses met the three pre-defined co-primary efficacy endpoints for efficacy. Greater proportions ofpatients treated with lorcaserin achieved 5% and 10% categorical weight loss as compared to patients d with placebo, and patients on lorcaserin achieved a significantly greater mean weight loss.

APD356-011 ("BLOSSOM") was a 52-week, placebo controlled study that evaluated the effect oftwo lorcaserin doses (10 mg BID and 10 mg QD) on categorical and total weight loss with concurrent or modification. Patients were randomized in a ratio of2: 1:2 to lorcaserin 10 mg BID, 10 mg QD, or placebo. Lorcaserin 10 mg QD and BID met the pre-defined mary cy endpoints. e 2 - Identifying Responders based on early weight loss.

An analysis y weight loss was performed, at each visit after baseline through Week 24, as a predictor ofultimate weight loss success, as defined by achieving at least about 5% weight loss at 52 weeks, or at least about 10% weight loss at 52 weeks.

The area under the curve (AUC) for the receiver operating characteristic (ROC) curve measures the balance between specificity and sensitivity by measuring how often a predictor ( e.g., Week 12 or Week 24 percent weight loss) and a successful outcome ( e.g., at least 5% or 10% weight loss at Week 52) are concordant.

At Week 12, the optimal thresholds were 4.6% and 5.9% weight loss for predicting at least 5% and at least 10% weight loss at Week 52. At Week 24, the optimal weight loss thresholds were 6.1 % and 8.5%, respectively (Table 1 and Table 2). Nondiabetic patients who ed at least 5% weight loss at Week 12, lost on average approximately 10.6 kilos (23 pounds) at Week 52, and approximately 86% and 50% of these patients respectively achieved at least 5% and 10% weight loss at Week 52. The ation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm positive and negative predictive values for this criterion were 85.5% and 74.0% for 5% weight loss at Week 52, and 49.8% and 95.3% for 10% weight loss at Week 52 (Table 3).

Table 1. AUCs for the ROC curves using percent weight change from baseline at each early visit (Weeks 2-24) as predictors for at least 5% weight loss at Week 52 serin 10mg BID) Percent Change from %Weight 95% Confidence AUC* SE Baseline at: Loss Interval Week2 1.5% 0.687 0.015 (0.658, 0.716) Week4 2.5% 0.753 0.014 (0.726, 0.780) Week8 3.9% 0.802 0.012 , 0.826) Week 12 4.6% 0.849 0.011 (0.828, 0.870) Week24 6.1% 0.912 0.008 (0.897, 0.927) Higher number sigmfies better prediction.

Table 2. AUCs for the ROC curves using percent weight change from baseline at each early visit (Weeks 2-24) as predictors for at least 10% weight loss at Week 52 (lorcaserin 10mg BID) Predictors: Percent Change from %Weight 95% Confidence Baseline at Loss AUC* SE al Week2 1.8 0.707 0.014 (0.680, 0.735) Week4 3.2 0.777 0.014 (0.752, 0.802) Week8 4.7 0.829 0.011 (0.807, 0.851) Week 12 5.9 0.866 0.010 (0.845, 0.885) Week24 8.5 0.929 0.007 (0.915, 0.942) " Higher number sigmfies better prediction.

Table 3 and Table 4 provide the sensitivity, specificity, positive predicted value (PPV) and negative predictive value (NPV) at Weeks 12 and 24 for at least about % and at least about 10% weight loss at Week 52 in ent studies. The rounded percent weight loss at Week 12 for at least 5% and at least about 10% weight loss at Week 52 are about 5% and about 6%, respectively. Using the about 6% weight loss at Week 12 as a criterion enhances the PPV for both about 5% and about 10% categorical weight loss at Week 52, but at the expense ofexcluding about 10% and about 4% more ofthe about % categorical responders at Week 52 in patients without and with es, respectively, [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm ed set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm based upon NPV. The rounded optimal thresholds at Week 24 for at least about 5% and at least about 10% weight loss at Week 52 are about 6% and about 9%, respectively. Using the 9% weight loss ion at Week 24 enhances the PPV for both about 5% and about % categorical weight loss at Week 52, but at the expense ofexcluding about 19% and about 9% more ofthe about 5% categorical responders at Week 52 in patients without and with diabetes, respectively, based upon NPV. As described below, ifat least about a 5% weight loss criterion is applied, patients achieving this milestone will achieve an average ofabout 10.8% weight loss in patients t diabetes and about 9.1 % weight loss in patients with diabetes at Week 52.

Table 3. Sensitivity and Specificity Analyses for lorcaserin 10mg BID use Week k 24 responder status as a predictor for Week 52 (Pooled BLOOM and M Studies) Criteria Sensitivity Specificity PPV NPV Week 12: 5% and Week 52: 5% 76.2% 84.0% 85.5% 74.0% Week 12: 5% and Week 52: 10% 91.2% 66.1% 49.8% 95.3% Week 12: 6% and Week 52: 5% 61.3 90.9 89.3 65.4 Week 12: 6% and Week 52: 10% 82.4 78.4 58.4 92.4 Week 24: 6% and Week 52: 5% 83.4 84.9 89.0 77.7 Week 24: 6% and Week 52: 10% 96.5 62.1 52.5 97.6 Week 24: 9% and Week 52: 5% 52.8 97.2 96.5 58.5 Week 24: 9% and Week 52: 10% 82.7 89.2 76.9 92.2 Note: Only patients with observed Week 12 (Week 24) data are included in the above analyses.

[Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm Table 4. Sensitivity and Specificity Analyses for lorcaserin 10mg BID use Week 12/Week 24 responder status as a predictor for Week 52 (BLOOMDM Study) Criteria ivity Specificity PPV NPV Week 12: 5% and Week 52: 5% 61.1% 81.9% 70.5% 74.8% Week 12: 5% and Week 52: 10% 70.0% 71.8% 35.9% 91.4% Week 12: 6% and Week 52: 5% 46.7 91.3 79.2 70.7 Week 12: 6% and Week 52: 10% 60.0 83.6 45.3 90.2 Week 24: 6% and Week 52: 5% 65.9 83.3 76.3 75.0 Week 24: 6% and Week 52: 10% 86.8 72.8 43.4 95.8 Week 24: 9% and Week 52: 5% 37.5 99.1 97.1 66.0 Week 24: 9% and Week 52: 10% 65.8 94.3 73.5 92.0 Note: Only patients with ed Week 12 (Week 24) data are included in the above analyses The proportion ofnon-diabetic patients who ed at least 5% total body weight loss at Week 52 was greater for Week 12 responders than for Week 12 nonresponders (see Table 5 and Figure 1).

Table 5 Week 52 Week 12 Completed Week 12a (MITT with LOCF) 2: 5% wt loss l,251/2,537 (49.3%) l,070/1,251 (85.5%) < 5% wt loss l,286/2,537 (50.7%) 335/1,286 (26.0%) aPercentage calculated based on number ofpatients with observed Week 12 data Example 3 - Week 52 Outcomes for Those Achieving at least 5% Weight Loss at Week 12 ] In patients t type 2 diabetes mellitus (T2DM), proportions achieving 2:5% weight loss and weight loss at Week 52 for (R)chloromethyl-2,3,4,5- tetrahydro-lHbenzazepine hydrochloride salt drate ("drug") and placebo patients were 47 vs. 23% and 5.8 vs. 2.5kg, respectively (MITT-LOCF). s in patients with T2DM were 38 vs.16% and 4.7 vs.1.9kg, respectively. Proportions meeting the 2:5% weight loss at Week 12 criterion were 49.3% and 35.9% for drug patients [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm ation] kjm Unmarked set by kjm without and with T2DM, respectively, and 22.6% and 11.5% for placebo patients. Week 52 weight loss in non-diabetic drug Week 12 responders was 10.6 kg (23 lbs), and 86% and 50% ofpatients achieved at least 5% and 10% weight loss. In diabetic drug Week 12 responders, s were 9.3kg (20 lbs), 71 %, and 36%.

Week 52 reductions in FPG and AlC in diabetic drug Week 12 responders were 29.3 mg/dL and 1.2%, and were 7.8 mg/dL and 0.4% in drug Week 12 ders with impaired fasting glucose (IFG) at baseline. Week 52 reductions in systolic and diastolic BP and heart rate were 3.4 mmHg, 2.5 mmHg, and 2.5 BPM in non-diabetic drug Week 12 responders, and 2.6mmHg, 1.9 mmHg, and 3.2 BPM in drug Week 12 responders with T2DM. ingly, achievement of2:5% weight loss by Week 12 is a strong predictor ofrobust one-year responses in , cardiovascular vital signs, and ia.

In one embodiment, based upon the predictive value for 2:5% weight loss at Week 52, drug should not be administered to an individual not losing at least about 5% at Week 12 (i.e., are not Week 12 responders).

Tables 6 and 7, below, present weight loss, vital sign, and glycemic changes at Week 52 in pooled patients without diabetes, patients with T2DM, and pooled patients with impaired fasting glucose (IFG; 2:100 mg/dL) who were Week 12 responders.

Table 6: Drug 10 mg BID patients Patients Patients Patients without with with T2DM T2DM IFG N BL W52 N BL W52 N BL W52 Change Change Change Weight Loss 1251 78 170 2:5% (%) 85.5 70.5 88.8 2:10% (%) 49.8 35.9 52.4 kg 99.0 -10.6 102.3 -9.3 104.3 -11.2 FPG 94.7 -2.2 156.4 -29.3 107.2 -7.8 (mg/dL) AlC (%) 5.6 -0.18 7.9 -1.2 5.8 -0.11 SBP 122.0 -3.4 129.0 -2.6 124.2 -1.7 (mmHg) DBP 77.6 -2.5 80.1 -1.9 78.6 -1.5 (mmHg) Heart Rate 69.0 -2.5 73.3 -3.2 70.8 -3.7 (bpm) Total 196.3 -1.7 168.4 -0.7 199.2 -2.3 terol (mg/dL)* LDL-C 115.4 1.1 91.9 1.4 116.5 2.5 (mg/dL)* Triglycerides 139.7 -14.5 163.9 -17.8 150.7 -15.5 (mg/dL)* HDL-C 53.4 4.6 46.0 8.8 52.8 2.1 (mg/dL)* *For lipid parameters used percent change from baseline at Week 52 Table 7: Placebo Patients: Patients Patients Patients without with with T2DM T2DM IFG N BL W52 N BL W52 N BL W52 Change Change Change Weight Loss 541 25 61 2:5% (%) 76.2 60.0 78.7 2:10% (%) 38.6 28.0 50.8 kg 100.3 -9.5 103.1 -7.5 102.2 -10.5 FPG 95.1 -1.2 157.2 -24.2 108.8 -7.5 (mg/dL) AlC (%) 5.6 -0.15 8.1 -1.1 5.8 -0.07 SBP 123.7 -3.6 129.5 -4.2 127.4 -4.6 (mmHg) DBP 78.0 -2.4 80.8 -2.6 79.3 -2.5 (mmHg) Heart Rate 69.1 -2.5 70.6 0.0 70.4 -5.7 (bpm) Total 197.5 -0.5 167.5 0.0 208.3 -1.7 Cholesterol (mg/dL)* LDL-C 115.4 1.7 90.1 5.6 122.5 1.1 Triglycerides 143.4 -10.5 160.7 -15.6 170.0 -14.5 (mg/dL)* HDL-C 53.4 5.7 45.2 11.7 52.4 4.5 (mg/dL)* *For lipid parameters used percent change from baseline at Week 52 Proportions ents without diabetes with a Week 12 observation who had at least 5% weight loss at Week 12 (Week 12 responders), lorcaserin vs. placebo, were 49.3% vs. 22.6% (Table 8). Week 52 weight loss in lorcaserin Week 12 responders without diabetes was 10.6kg (23 lbs), with 86% and 50% achieving at least 5% and 10% [Annotation] kjm None set by kjm [Annotation] kjm ionNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm weight loss, respectively (Table 9 and Figure 1). Proportions ofWeek 12 responders with type 2 diabetes, lorcaserin vs. placebo, were 35 .9% vs. 11.5%. Week 52 weight loss in lorcaserin Week 12 responders with type 2 es was 9.3kg (20 lbs), with 71 % and 36% achieving 5% and 10% weight loss, respectively. Figure 2 shows weight loss through Week 52 for Week 12 ders and non-responders with and without diabetes in both treatment groups. In patients with type 2 diabetes, change in HbAlc at Week 52 was -1.2% for lorcaserin Week 12 ders vs. -0.84% in non-responders (see Table 4).

Week 52 reductions in systolic and diastolic blood pressure and heart rate were 3.4 mmHg, 2.5 mmHg, and 2.5 bpm in lorcaserin responders without diabetes, and 2.6 mmHg, 1.9 mmHg, and 3.2 bpm in lorcaserin responders with type 2 diabetes (Table 10).

Table 8. (%) of Patients with Observed Week 12 Data N N with observed Week 12 Week 12 Randomized Week 12 dataa Responderb Non- Responderb Pooled BLOOM and BLOSSOM Studies erin 3198 2537 ) 1251 (49.3%) 1286 (50.7%) lOmgBID Placebo 3190 2393 (75.0%) 541 (22.6%) 1852 (77.4%) BLOOM-DM Study Lorcaserin 256 217 (84.8%) 78 (35.9%) 139 (64.1 %) lOmgBID Placebo 253 217 (85.8%) 25 (11.5%) 192 (88.5%) aPercentage calculated based on number randomized. bWeek 12 Responder= at least 5% weight loss at Week 12; percentage calculated based on number ofpatients with observed Week 12 data.

[Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm Table 9. Week 52 Results by Week 12 Responder Status (lorcaserin 10 mg BID) Week 52 Weight Mean (SE) Mean (SE) Week 12 status Change Percent Change % 10% from from Baseline, Responder Responder ne, kg % Pooled BLOOM and M Studies: (MITT with LOCF) Responder (2:5% 85.5% 49.8% -10.63 (0.18) -10.84 (0.18) weight loss) Non-responder 26.0% 4.7% -2.76 (0.12) -2.73 (0.12) (<5%) Pooled BLOOM and BLOSSOM Studies: (Completers Population) Responder (2:5% 85.8 55.9 -11.31 (0.21) -11.52 (0.21) weight loss ) sponder 35.9 7.4 -3.50 (0.18) -3.44 (0.18) (<5%) BLOOM-DM Study: (MITT with LOCF) Responder (2:5% 70.5 35.9 -9.26 (0.77) -9.07 (0.70) weight loss) Non-responder 25.2 8.6 -3.20 (0.36) -3.13 (0.35) (<5%) BLOOM-DM Study: (Completers tion) Responder (2:5%) 70.8 40.0 -9.77 (0.89) -9.49 (0.80) Non-responder 29.0 10.0 -3.45 (0.44) -3.36 (0.42) (<5%) aWeek 12 Responder= at least 5% weight loss at Week 12; percentage calculated based on number ofpatients with observed Week 12 data.

Note: Only patients with observed Week 12 data are included in the above analyses.

[Annotation] kjm None set by kjm ation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm Table 10. Week 52 Secondary Endpoint s by Week 12 Responder Status (lorcaserin 10 mg BID) Week 52 Change from Baseline Mean (SE) Week 12 status Systolic BP Diastolic BP Heart Rate HbAlc t T2DM Responder (5%) -3.39 (0.34) -2.52 (0.25) -2.45 (0.26) -0.18 (0.01) Nonresponder (5%) -0.82 (0.34) -1.02 (0.25) -0.29 (0.26) -0.05 (0.01) With T2DM Responder (5%) -2.59 (1. 73) -1.91 (1.01) -3.24 (1.21) -1.20 (0.11) Nonresponder (5%) -0.55 (1.11) -1.07 (0.86) -0.87 (0.73) -0.84 (0.09) Note: Only patients with observed Week 12 data are included in the above analyses.

Example 4 - Salts Form III ofCompound 1 hydrochloride salt hemihydrate can be prepared as described in , , , WO 2007/120517, , and , , W0/2011/153206, W0/2012/030939, W0/2012/030938, W0/2012/030951, W0/2012/030953, W0/2012/030957, and W0/2012/030927, each ofwhich is incorporated herein by reference in its entirety. s synthetic routes to (R)chloromethyl-2,3,4,5-tetrahydro-lH- 3-benzazepine, its related salts, enantiomers, lline forms, and intermediates, have been reported in , , , WO 2007/120517, , and , , W0/2011/153206, 2/030939, W0/2012/030938, W0/2012/030951, W0/2012/030953, W0/2012/030957, and W0/2012/030927, each ofwhich is incorporated herein by nce in its entirety.

Other uses ofthe disclosed methods will become apparent to those in the art based upon, inter alia, a review ofthis patent document.

Claims

What is claimed is:

1. Use of (R)chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof in the manufacture of a medicament for the therapeutic ent of an individual, wherein said therapeutic treatment is weight management; wherein said medicament is provided for oral administration to the individual at a dose equivalent to 20 mg of (R)chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine hloride per day; wherein said medicament is provided for administration in combination with a reduced-calorie diet; n said individual has been selected for treatment as previously being determined to have achieved at least 5% weight loss within 12 weeks of treatment with (R)- 8-chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a ceutically acceptable salt, solvate or hydrate f at a dose equivalent to 20 mg of (R)chloromethyl- 2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride per day, whereby achievement of at least 5% weight loss by week 12 correlates with a likelihood of the individual achieving an additional decrease in an assessment of weight after about one year; and wherein said dual has an initial body mass index (BMI) of >27 kg/m2 prior to treatment with (R)chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

2. The use of claim 1, n the individual has an initial BMI of >30 kg/m2.

3. The use of claim 1 or claim 2, n the individual has at least one weight related comorbid condition.

4. The use of claim 3, wherein the weight related comorbid condition is ed from: hypertension, dyslipidemia, and type 2 diabetes.

5. The use of any one of claims 1-4, wherein said weight management comprises weight loss.

6. The use of any one of claims 1-4, wherein said weight management comprises controlling weight gain.

7. The use of any one of claims 1-4, wherein said weight ment comprises maintenance of weight loss.

8. The use of any one of claims 1-7, wherein the medicament is provided for stration in combination with a program of regular exercise.

9. Use of (R)chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, e or hydrate thereof in the manufacture of a medicament for the therapeutic treatment of an individual, wherein said therapeutic treatment is decreasing food intake; wherein said medicament is provided for oral administration to the individual at a dose equivalent to 20 mg of (R)chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride per day; wherein said medicament is provided for administration in combination with a reduced-calorie diet; wherein said individual has been selected for treatment as previously being determined to have achieved at least 5% weight loss within 12 weeks of treatment with (R)- 8-chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, e or hydrate f at a dose equivalent to 20 mg of (R)chloromethyl- 2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride per day, whereby achievement of at least 5% weight loss by week 12 correlates with a likelihood of the individual achieving an additional decrease in an assessment of weight after about one year; and n said individual has an initial body mass index (BMI) of >27 kg/m2 prior to treatment with chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a ceutically acceptable salt, solvate or hydrate f.

10. The use of claim 9, wherein the individual has an initial BMI of >30 kg/m2.

11. The use of claim 9 or claim 10, wherein the individual has at least one weight related comorbid condition.

12. The use of claim 11, wherein the weight related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 diabetes.

13. The use of any one of claims 9-12, wherein the medicament is provided for administration in combination with a program of regular exercise.

14. Use of (R)chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof in the manufacture of a medicament for the therapeutic treatment of an individual, wherein said eutic treatment is inducing satiety; n said medicament is provided for oral administration to the individual at a dose equivalent to 20 mg of (R)chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride per day; wherein said medicament is provided for stration in combination with a reduced-calorie diet; wherein said individual has been selected for treatment as previously being determined to have achieved at least 5% weight loss within 12 weeks of treatment with (R)- 8-chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof at a dose lent to 20 mg of (R)chloromethyl- 2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride per day, whereby achievement of at least 5% weight loss by week 12 correlates with a likelihood of the individual ing an additional decrease in an assessment of weight after about one year; and wherein said individual has an initial body mass index (BMI) of >27 kg/m2 prior to treatment with (R)chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

15. The use of claim 14, wherein the individual has an l BMI of >30 kg/m2.

16. The use of claim 14 or claim 15, wherein the individual has at least one weight related comorbid condition.

17. The use of claim 16, n the weight related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 es.

18. The use of any one of claims 14-17, wherein the medicament is provided for stration in combination with a program of regular exercise.

19. Use of (R)chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof in the manufacture of a ment for the therapeutic treatment of an individual, n said eutic treatment is the ent of y; wherein said medicament is provided for oral administration to the individual at a dose equivalent to 20 mg of (R)chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride per day; wherein said medicament is provided for administration in combination with a reduced-calorie diet; wherein said individual has been selected for treatment as usly being determined to have achieved at least 5% weight loss within 12 weeks of treatment with (R)- 8-chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof at a dose equivalent to 20 mg of (R)chloromethyl- 2,3,4,5-tetrahydro-1Hbenzazepine hydrochloride per day, whereby achievement of at least 5% weight loss by week 12 correlates with a likelihood of the individual achieving an additional decrease in an assessment of weight after about one year; and wherein said individual has an initial body mass index (BMI) of >30 kg/m2 prior to treatment with chloromethyl-2,3,4,5-tetrahydro-1Hbenzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.

20. The use of claim 19, wherein the individual has at least one weight related comorbid condition.

21. The use of claim 20, wherein the weight related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 diabetes.

22. The use of any one of claims 19-21, wherein the medicament is provided for administration in combination with a program of r exercise. [Annotation] kjm None set by kjm [Annotation] kjm ionNone set by kjm [Annotation] kjm Unmarked set by kjm [Annotation] kjm None set by kjm [Annotation] kjm MigrationNone set by kjm [Annotation] kjm Unmarked set by kjm